WO2002006254A1 - Tetrazole derivatives - Google Patents

Tetrazole derivatives Download PDF

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Publication number
WO2002006254A1
WO2002006254A1 PCT/EP2001/007692 EP0107692W WO0206254A1 WO 2002006254 A1 WO2002006254 A1 WO 2002006254A1 EP 0107692 W EP0107692 W EP 0107692W WO 0206254 A1 WO0206254 A1 WO 0206254A1
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Prior art keywords
tetrazol
formula
compound
amide
carboxylic acid
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Application number
PCT/EP2001/007692
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French (fr)
Inventor
Synese Jolidon
Vincent Mutel
Eric Vieira
Juergen Wichmann
Original Assignee
F. Hoffmann-La Roche Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to KR10-2003-7000350A priority Critical patent/KR100504292B1/en
Priority to BR0112465-0A priority patent/BR0112465A/en
Priority to MXPA03000221A priority patent/MXPA03000221A/en
Priority to AU7847201A priority patent/AU7847201A/en
Priority to JP2002512158A priority patent/JP3971298B2/en
Priority to AU2001278472A priority patent/AU2001278472B2/en
Priority to EP01956515A priority patent/EP1303499B1/en
Priority to CA002415673A priority patent/CA2415673A1/en
Priority to DE60121447T priority patent/DE60121447T2/en
Publication of WO2002006254A1 publication Critical patent/WO2002006254A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C—CHEMISTRY; METALLURGY
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is concerned with 2H-tetrazole-5-yl-amide derivatives of the general formula
  • R 1 signifies hydrogen, lower alkyl, -(CH 2 ) n -CF 3 , -(CH 2 ) n -CHF 2) , -(CH 2 ) n -CN, -(CH 2 ) n -cycloalkyl, -(CH 2 ) n -O-lower alkyl, -(CH 2 ) n -O-cycloalkyl or -(CH 2 ) n -C(O)O-lower alkyl;
  • R" signifies hydrogen, lower alkyl, lower alkoxy, halogen, -C(O)-lower alkyl, -C(O)OH, -C(O)O-lower alkyl, -NR 3 R 4 or -C(O)-NR 3 R 4 and wherein R 3 and R 4 may be independently from each other hydrogen or lower alkyl;
  • X signifies -O-, -S-, -CH 2 , -OCH 2 - or two hydrogen atoms not forming a bridge;
  • n 0, 1, 2, 3 or 4; as well as with their pharmaceutically acceptable salts.
  • the central nervous system In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
  • L-glutamic acid the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes.
  • the glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand- controlled ion channels.
  • the metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors. At present, eight different members of these mGluRs' are known and of these some even have sub-types.
  • these eight receptors can be sub-divided into three sub-groups: mGluRl and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR ⁇ , mGluR7 and mGluR ⁇ belong to group III.
  • Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
  • treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
  • Further treatable indications are Huntington's chorea, amyo rophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
  • ALS amyo rophic lateral sclerosis
  • dementia caused by AIDS
  • eye injuries eye injuries
  • retinopathy idiopathic parkinsonism or parkinsonism caused by medicaments
  • glutamate-deficiency functions such as e.g. muscle spasms, convulsion
  • Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
  • the following structures are encompassed from the scope of compounds of formula I:
  • Preferred compounds of formula I in the scope of the present invention are those, in which X signifies 2 hydrogen atoms not forming a bridge (formula IA).
  • X signifies 2 hydrogen atoms not forming a bridge
  • 9H-xanfhene-9-carboxylic acid (2-methyl-2H-tetrazol-5-yl)-amide
  • 9H-xanthene-9-carboxy ⁇ ic acid (2-ethyl-2H-tetrazol-5-yl)-amide
  • 9H-xanthene-9-carboxylic acid (2-cyclopropylmethyl-2H-tetrazol-5-yl)-amide
  • 9H-xanthene-9-carboxylic acid (2-isopropyl-2H-tetrazol-5-yl)-amide
  • a preferred enbodiment of the ppsent invention are further compounds of formula
  • the invention embraces all stereoisomeric forms in addition to the racemates.
  • lower alkyl used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 - 7 carbon atoms, preferably with 1 - 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
  • lower alkoxy denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
  • cycloalkyl embraces cyclic alkylene groups with 3 to 7 carbon atoms.
  • the pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt.
  • Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I.
  • Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation or pharmaceutically acceptable salts of acidic compounds.
  • Scheme 1 gives an overview of the manufacture of the compounds of formula I.
  • the manufacture of representative compounds of formula I is described in detail in examples 1 — 28.
  • the starting material is known or may be prepared by known methods.
  • the compounds of formula I may be prepared in conventional manner by methods, known in the art.
  • the compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor agonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, cognitive diorders and memory deficits, as well as acute and chronic pain.
  • Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
  • Further treatable indications are Alzheimer's disease, Huntington's chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. It has been shown that the compounds of examples 1 - 28 show agonistic activities, as measured in the assay described below, of 10 ⁇ M or less, typically 1 ⁇ M or less, and ideally of 0.3 ⁇ M or less.
  • the inhibition (antagonists) or activation (agonists) curves were fitted with a four parameter logistic equation giving EC5 0 , IC 50 and Hill coefficient using the iterative non linear curve fitting software Origin (Microcal Software Inc., Northampton, MA, USA).
  • the compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the admini- stration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
  • Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described.
  • N-(2-Methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide To a stirred solution of 5-amino-2-methyl-2H-tetrazole (0.50 g, 5.05 mmol), pyridine (0.48 g, 6.06 mmol) and DMAP (0.06 g, 0.51 mmol) in dichloromethane (30 ml) was added at 0°C diphenylacetyl chloride (1.16 g, 5.05 mmol). Stirring was continued at RT for 2 h, the reaction mixture was poured into sat. NaHCO 3 solution (50 ml) and extracted with dichloromethane (3 x 50 ml).
  • 5-Amino-2-meth ⁇ l-2H-tetrazole is obtained from 5-aminotetrazole-monohydrate and methyl iodide by the method of R.A. Henri et al., J.Amer.Chem.Soc. 76, 923 (1954).
  • 5-Amino-2-ethyl-2H-tetrazole is prepared according to the method of R.N.Butler et al, J.Chem.Res.Synopsis 1988, 188.
  • Example A Tablets of the following composition are produced in a conventional manner:
  • Active ingredient 200 Powdered, lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate
  • the active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed.
  • the final mixture is filled into hard gelatine capsules of suitable size.

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Abstract

The present invention is concerned with 2H-tetrazole-5-yl-amide derivatives of general formula (I) wherein R1 signifies hydrogen, lower alkyl, -(CH¿2?)n-CF3, -(CH2)n-CHF2, -(CH2)n-CN, -(CH2)n-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-cycloalkyl or -(CH2)n-C(O)O-lower alkyl; R?2¿ signifies hydrogen, lower alkyl, lower alkoxy, halogen, -C(O)-lower alkyl, -C(O)OH, -C(O)O-lower alkyl, -NR3R4 or -C(O)-NR3R4 and wherein R?3 and R4¿ may be independently from each other hydrogen or lower alkyl; X signifies -O-, -S-, -CH¿2?, -OCH2- or two hydrogen atoms not forming a bridge; and n signifies 0, 1, 2, 3 or 4; as well as with their pharmaceutically acceptable salts. It has been found that the compounds of general formula (I) are group 1 metabotropic glutamate receptor agonists (mGluR) and are therefore useful in the treatment of corresponding CNS-disorders.

Description

Tetrazole derivatives
The present invention is concerned with 2H-tetrazole-5-yl-amide derivatives of the general formula
Figure imgf000002_0001
wherein R1 signifies hydrogen, lower alkyl, -(CH2)n-CF3, -(CH2)n-CHF2) , -(CH2)n-CN, -(CH2)n-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-cycloalkyl or -(CH2)n-C(O)O-lower alkyl;
R" signifies hydrogen, lower alkyl, lower alkoxy, halogen, -C(O)-lower alkyl, -C(O)OH, -C(O)O-lower alkyl, -NR3R4 or -C(O)-NR3R4 and wherein R3 and R4 may be independently from each other hydrogen or lower alkyl;
X signifies -O-, -S-, -CH2, -OCH2- or two hydrogen atoms not forming a bridge; and
n signifies 0, 1, 2, 3 or 4; as well as with their pharmaceutically acceptable salts.
These compounds and their salts are novel and are distinguished by valuable therapeutic properties. It has been found that the compounds of general formula I are group 1 metabotropic glutamate receptor agonists (mGluR).
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor. L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand- controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors. At present, eight different members of these mGluRs' are known and of these some even have sub-types. On the basis of structural parameters, the different second messager signalling pathways and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluRl and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluRό, mGluR7 and mGluRδ belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington's chorea, amyo rophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments. The following structures are encompassed from the scope of compounds of formula I:
Figure imgf000003_0001
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000004_0004
wherein R and R are as defined in formula I above.
Preferred compounds of formula I in the scope of the present invention are those, in which X signifies 2 hydrogen atoms not forming a bridge (formula IA). The following are examples of such compounds:
N-(2-methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-ethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-isopropyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, 2,2-diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetamide, 2,2-diphenyl-N-(2-propyl-2H-tetrazol-5-yl)-acetamide, N-(2-methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-tert-butyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
N-(2-difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide and (5-diphenylacetylamino-tetrazol-2-yl)-acetic acid methyl ester.
Compounds of formula I, wherein X signifies -O- (formula IB) are further preferred.
Examples of such compounds are:
9H-xanfhene-9-carboxylic acid (2-methyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxyϊic acid (2-ethyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-cyclopropylmethyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-isopropyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid [2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-amide, 9H-xanthene-9-carboxylic acid (2-propyl-2H-tetrazol-5-yl) -amide, 9H-xanthene-9-carboxylic acid (2-methoxymethyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-tert-butyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-difluoromethyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-cyanomethyl-2H-tetrazol-5-yl)-amide, {5-[(9H-xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester, (RS)-l~methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide, (RS)-2-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide and (RS)-4-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Compounds of formula I, wherein X signifies -S- (formula IC) are further preferred, for example the following compound: 9H-thioxanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
Further preferred are compounds of formula I, wherein X signifies -CH2- (formula ID), for example the following compound: 9, 10-dihydro-anthracene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide. Preferred are further compounds of formula I, wherein X signifies -OCH2- (formula IE), for example the following compound:
(RS)-6,ll-dihydro-dibenzo[b,e]oxepine-ll-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)- amide.
A preferred enbodiment of the ppsent invention are further compounds of formula
IA, IB, IC, ID and IE, wherein R2 signifies hydrogen.
The invention embraces all stereoisomeric forms in addition to the racemates.
The term "lower alkyl" used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 - 7 carbon atoms, preferably with 1 - 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term "lower alkoxy" denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term "cycloalkyl" embraces cyclic alkylene groups with 3 to 7 carbon atoms..
The compounds of general formula I and their pharmaceutically acceptable salts can be manufactured by processes, which comprises
a) reacting a compound of formula
Figure imgf000006_0001
with a compound of formula
Figure imgf000006_0002
to a compound of formula
Figure imgf000007_0001
wherein the substituents have the significances set forth above, and, if desired, converting a functional group in a compound of formula I into another functional group and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
In accordance with process variant described above to a stirred solution of a compound of formula II, for example of 5-amino-2-methyl-2H-tetrazole, 5-amino-2- ethyl-2H-tetrazole or 5-amino-2-cyclopropylmethyl-2H-tetrazole in dichloromethane in the presence of pyridine and DMAP (2,2-bis(hydroxymethyl)propionic acid) the corresponding compound of formula III, for example diphenylacetyl chloride or 9H- xanthene-9-carbonyl chloride is added. The reaction is carried out at about 0 °C
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation or pharmaceutically acceptable salts of acidic compounds.
Scheme 1 gives an overview of the manufacture of the compounds of formula I. The manufacture of representative compounds of formula I is described in detail in examples 1 — 28. The starting material is known or may be prepared by known methods. The compounds of formula I may be prepared in conventional manner by methods, known in the art. Scheme 1
Figure imgf000008_0001
Figure imgf000008_0002
The substituents have the significances given earlier.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor agonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, cognitive diorders and memory deficits, as well as acute and chronic pain. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Alzheimer's disease, Huntington's chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. It has been shown that the compounds of examples 1 - 28 show agonistic activities, as measured in the assay described below, of 10 μM or less, typically 1 μM or less, and ideally of 0.3 μM or less.
Examples of such compounds are
Figure imgf000009_0001
Test Method cDNA encoding for rat mGlula receptor obtained from Prof. S. Nakanishi (Kyoto, Japan) was transiently transfected into EBNA cells using a procedure described by Schlaeger & Christensen, 1998. [Ca2+]i measurement were performed on mGlula transfected EBNA cells after incubation of the cells with Fluo-3 AM (0.5 μM final concentration) for 1 hour at 37°C followed by 4 washes with assay buffer (DMEM supplemented with Hank's salt and 20 mM HEPES). [Ca +]i measurement were done using a fluorometric imaging plate reader (FLIPR, Molecular Devices Corporation, La Jolla, CA, USA). When compounds were evaluated as antagonists they were tested against 10 μM glutamate as agonist.
The inhibition (antagonists) or activation (agonists) curves were fitted with a four parameter logistic equation giving EC50, IC50 and Hill coefficient using the iterative non linear curve fitting software Origin (Microcal Software Inc., Northampton, MA, USA).
E.-J. Schlaeger and K. Christensen Transient gene expression in mammalian cells grown in serum-free suspension culture. Cytotechnology, 15: 1-13, 1998. The compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the admini- stration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of medicaments, especially for the control or prevention of acute and or chronic neurological disorders of the aforementioned kind, is also an object of the invention.
Example 1
N-(2-Methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide To a stirred solution of 5-amino-2-methyl-2H-tetrazole (0.50 g, 5.05 mmol), pyridine (0.48 g, 6.06 mmol) and DMAP (0.06 g, 0.51 mmol) in dichloromethane (30 ml) was added at 0°C diphenylacetyl chloride (1.16 g, 5.05 mmol). Stirring was continued at RT for 2 h, the reaction mixture was poured into sat. NaHCO3 solution (50 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with brine (70 ml), dried (Na2SO ) and evaporated. The crude product was crystallized from ethyl acetate/hexane to give the title compound (0.83 g, 56 %) as a white solid, m.p. 218 °C (dec.) and MS: m/e = 293.1 (M+H+).
Example 2
9H-Xanthene-9-carboxylic acid (2-methyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 247 °C (dec.) and MS: m/e = 307.1 (M+) was prepared in accordance with the general method of example 1 from 5-amino-2-methyl- 2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 3
N-(2-Ethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
The title compound, white solid, m.p. 169-170 ° and MS: (neg. ions): m/e = 306.2 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl- 2H-tetrazole and diphenylacetyl chloride.
Example 4
9H-Xanfhene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 228 °C (dec.) and MS: (neg. ions): m/e = 320.0 (M+- H) was prepared in accordance with the general method of example 1 from 5-amino-2- ethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride. Example 5 N-(2-Cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
The title compound, white solid, m.p. 147-148 ° and MS: m/e = 334.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2- cyclopropylmethyl-2H-tetrazole and diphenylacetyl chloride.
Example 6
9H-Xanthene-9-carboxylic acid (2-cyclopropylrnethyl-2H-tetrazoi-5-yl)-arnide
The title compound, white solid, m.p. 222-224 °C and MS: (neg. ions): m/e = 346.2 (M+- H) was prepared in accordance with the general method of example 1 from 5-amino-2- cyclopropylmethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 7
N-(2-Isopropyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
The title compound, white solid, m.p. 175-177 ° and MS: (neg. ions): m/e = 320.2 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2- isopropyl-2H-tetrazole and diphenylacetyl chloride.
Example 8
9H-Xanthene-9-carboxylic acid (2-isopropyl-2H-tetrazol-5-yl) -amide
The title compound, white solid, MS: (neg. ions): m/e = 334.2 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-isopropyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 9
2,2-Diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetamide
The title compound, white solid, m.p. 146-148 ° and MS: (neg. ions): m/e = 360.0 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-(2,2,2- trifluoroethyl)-2H-tetrazole and diphenylacetyl chloride. Example 10
9H-Xanthene-9-carboxylic acid [2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl] -amide
The title compound, white solid, m.p. 209-210 ° and MS: (neg. ions): m/e = 374.1 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-(2,2,2- trifluoroethyl)-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 11
2,2-Diphenyl-N-(2-propyl-2H-tetrazol-5-yl)-acetamide
The title compound, white solid, m.p. 124-125 ° and MS: (neg. ions): m/e = 320.0 (M+-H) was prepared in accordance with the general method of example 1 from 5~amino-2~propyl- 2H-tetrazole and diphenylacetyl chloride.
Example 12
9H-Xanthene-9-carboxylic acid (2-propyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 208-209 ° and MS: (neg. ions): m/e = 334.1 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-propyl- 2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 13
N-(2-Methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
The title compound, white solid, m.p. 127-128 ° and MS: (neg. ions): m/e = 322.2 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2- methoxymethyl-2H-tetrazole and diphenylacetyl chloride.
Example 14
9H-Xanthene-9-carboxylic acid (2-methoxymethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 221-222 ° and MS: (neg. ions): m/e = 336.1 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2- methoxymethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride. Example 15
N-(2-tert-Butyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
The title compound, white solid, m.p. 191-192 ° and MS: (neg. ions): m/e = 334.3 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-tert- butyl-2H-tetrazole and diphenylacetyl chloride.
Example 16
9H-Xanthene-9-carboxylic acid (2-tert-butyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 230-231 ° and MS: (neg. ions): m/e = 348.2 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-tert- butyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 17
N-(2-Difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
The title compound, white solid, m.p. 143-145 ° and MS: (neg. ions): m/e = 328.1 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2- difluoromefhyl-2H-tetrazole and diphenylacetyl chloride.
Example 18
9H-Xanthene-9-carboxylic acid (2-difluoromethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 168-169 ° and MS: (neg. ions): m/e = 342.0 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2- difluoromethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 19
N-(2-Cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide
The title compound, white solid, m.p. 173-174 ° and MS: m/e = 319.3 (M++H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2- yl)-acetonitrile and diphenylacetyl chloride. Example 20
9H-Xanthene-9-carboxylic acid (2-cyanomethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 204-205 ° and MS: m/e = 333.2 (M++H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2- yl)-acetonitrile and 9H-xanthene-9-carbonyl chloride.
Example 21
(5-Diphenylacetylamino-tetrazol-2-yl)-acetic acid methyl ester
The title compound, white solid, m.p. 168-169 ° and MS: (neg. ions): m/e = 350.2 (M+-H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol- 2-yl) -acetic acid methyl ester and diphenylacetyl chloride.
Example 22
{5-[(9H-Xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester
The title compound, white solid, m.p. 243-244 ° and MS: (neg. ions): m/e = 364.0 (M+-H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol- 2-yl)-acetic acid methyl ester and 9H-xanthene-9-carbonyl chloride.
Example 23
9,10-Dihydro-anthracene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 206-207 ° and MS: (neg. ions): m/e = 318.3 (M+-H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl- 2H-tetrazole and 9,10-dihydro-anfhracene-9-carbonyl chloride.
Example 24
(RS)-6,ll-Dihydro-dibenzo[b,e]oxepine-ll-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)- amide
The title compound, yellow solid, m.p. 158-159 ° and MS: (neg. ions): m/e = 334.1 (M+- H) was prepared in accordance with the general method of example 1 from 5-amino-2- ethyl-2H-tetrazole and 6,ll-dihydro-dibenzo[b,e]oxepine-ll-carbonyl chloride. Example 25
9H-Thioxanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 228 °C (dec.) and MS: (neg. ions): m/e = 320.0 (M+- H) was prepared in accordance with the general method of example 1 from 5-amino-2- ethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Example 26
(RS)- l-Methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 259-260 °C (dec.) and MS: (pos. ions): m/e = 352.3 (M++H) was prepared in accordance with the general method of example 1 from 5- amino-2-ethyl-2H-tetrazole and (RS)-l-mefhoxy-9H-xanthene-9-carbonyl chloride.
Example 27
(RS)-2-Methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 208-210 °C (dec.) and MS: (pos. ions): m/e = 352.3 (M++H) was prepared in accordance with the general method of example 1 from 5- amino-2-ethyl-2H-tetrazole and (RS)-2-methoxy-9H-xanthene-9-carbonyl chloride.
Example 28
(RS)-4-Methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide
The title compound, white solid, m.p. 239-240 °C (dec.) and MS: (pos. ions): m/e = 352.3 (M++H) was prepared in accordance with the general method of example 1 from 5- amino-2-ethyl-2H-tetrazole and (RS)-4-methoxy-9H-xanthene-9-carbonyl chloride.
Preparation of 2-substituted 5-amino-2H-tetrazoles
5-Amino-2-methγl-2H-tetrazole is obtained from 5-aminotetrazole-monohydrate and methyl iodide by the method of R.A. Henri et al., J.Amer.Chem.Soc. 76, 923 (1954).
5-Amino-2-ethyl-2H-tetrazole is prepared according to the method of R.N.Butler et al, J.Chem.Res.Synopsis 1988, 188.
5-amino-2-cyclopropγlmethyl-2H-tetrazole (amorphous white solid and MS: m/e = 139.1 (M+)) is similarly obtained from 5-aminotetrazole-monohydrate and cyclopropylmethyl iodide using the general method of R.N.Butler et al. (loc. ci ). 5-Amino-2-propyl-2H-tetrazole ( liquid; MS: m/e = 127.1 (M+)) is similarly obtained from 5-aminotetrazole-monohydrate and propyl iodide using the general method of R.N.Butler et al. (loc. cit).
5-Amino-2-isopropyl-2H-tetrazole (liquid, MS: m/e = 127.1 (M+)) is similarly obtained from 5r-aminotetrazole-monohydrate and isopropyl iodide using the general method of R.N.Butler et al. (loc. cit.).
5-Amino~2-tert-butyl-2H-tetr zole (white solid; m.p. = 114-115°) is obtained from 5- aminotetrazole-monohydrate and O-tert-butyl-N,N'-dicyclohexylisourea, according to the general method described by R.A. Henry et al., J.Heterocycl.Chem. 13, 391 (1976).
5-Amino-2-cyclopropylmethyl-2H-tetrazole (amorphous white solid and MS: m/e =
139.1 (M+)) is similarly obtained from 5-aminotetrazole-monohydrate and cyclopropylmethyl iodide using the general method of R.N.Butler et al. (loc. cit.).
5-Amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole (white solid; m.p. = 95-97°) is obtained from 5-aminotetrazole-monohydrate and 2,2,2-trifluoroethyl trifluoromethanesulfonate, in analogy to W.G. Reifenrath et al., J.Med.Chem. 23, 985 (1980).
5-Amino-2-methoxymethyl-2H-tetrazole (waxy solid; MS: m/e = 129.0 (M+)) is obtained from 5-aminotetrazole-monohydrate and chloromethyl methyl ether using the general method of R.N.Butler et al. (loc. cit.).
5-Amino-2-difluorotnethyl-2H-tetr zole (liquid; MS: m/e = 136.0 (M++H)) is obtained from 5-aminotetrazole-monohydrate and chlorodifluormethane, in analogy to the method described by V.G. Poludnenko et al., Chem.Heterocycl.Comp. (Engl.Transl.) 20, 422 (1984).
(5-Amino-tetrazol-2-yl)-acetonitrile (white solid; m.p.=105-106°) is obtained from 5- aminotetrazole-monohydrate and chloroacetonitrile, according to the method described by S.R. Buzilova et al., J.Org.Chem. USSR (Engl.Transl.) 25, 1375 (1989).(5-Amino-tetrazol- 2-yl)-acetic acid methyl ester (white solid; m.p.= 127-128°) is obtained from 5- aminotetrazole-monohydrate and methyl bromoacetate, in analogy to the method described by S.R. Buzilova et al. (loc.cit).
Preparation of the carbonyl chlorides
9, 1 Q-Dϊhydro-anthracene-9-carbonyl chloride was obtained by the method described in May & Mosettig, J.Amer.Chem.Soc; 70; 688, (1948). 6,1 l-Dihydro-dibenzo[b,e]oxepine-ll-carbonyl chloride (waxy solid) was obtained by the method described in Kumazawa et al, J.Med.Chem. 37, 804 (1994).
(RS)-4-Methoxy-9H-x nthene-9-carbonyl chloride was prepared according to general methods described in WO 9706178. 4-Methoxy-xanthene [J.Med.Chem., 32(10), 2357( 1989)] was deprotonated with lithium diisopropylamide in tetrahydrofuran followed by treatment with carbon dioxide. The resulting (RS)-4-methoxy-9H-xanthene-9- carboxylic acid (white solid and MS: m/e = 256.0 (M+)) was chlorinated with oxalyl chloride in toluene/DMF and yielded after evaporation of the reagent and solvents, the crude acid chloride, which was directly used without further purification.
(RS)-l-Methoxy-9H-xanthene-9-carbonyl chloride was similarly obtained by chlorination of (RS)-l-methoxy-9H-xanthene-9-carboxylic acid (white solid and MS: m/e = 257.1 (M++H) obtained from 1-methoxy-xanthene [J.Org.Chem., 22, 1644(1957)] ).
(RS)-2-Methoxy-9H-xanthene-9-carbonyl chloride was similarly obtained by chlorination of (RS)-2-methoxy-9H-xanthene-9-carboxylic acid (white solid and MS: m/e = 256.0 (M+) obtained from 2-methoxy-xanthene [J.Chem.Soc, 812(1956)].
Example A Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 100 Powdered, lactose 95
White corn starch 35
Polyvinylpyrrolidone 8
Na carboxymethylstarch 10
Magnesium stearate _2 Tablet weight 250 Example B Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 200 Powdered, lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate
Tablet weight 400
Example C
Capsules of the following composition are produced:
mg/Capsule
Active ingredient 50
Crystalline, lactose 60
Microcrystalline cellulose 34
Talc 5
Magnesium stearate JL Capsule fill weight 150
The active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved and thereafter talc and magnesium stearate are admixed. The final mixture is filled into hard gelatine capsules of suitable size.

Claims

Claims
1. Compounds of the general formula
Figure imgf000020_0001
wherein R1 signifies hydrogen, lower alkyl, -(CH2)n-CF3, -(CH2)n-CHF2, , -(CH2)n-CN, -(CH2)n-cycloalkyI, -(CH2)n-O-lower alkyl, -(CH2)n-O-cycloalkyl or -(CH2)n-C(O)O-lower alkyl;
R2 signifies hydrogen, lower alkyl, lower alkoxy, halogen, -C(O)-lower alkyl, -C(O)OH, -C(O)O-lower alkyl, -NR3R4 or -C(O)-NR3R4 and wherein R3 and R4 may be independently from each other hydrogen or lower alkyl;
X signifies -O-, -S-, -CH2, -OCH - or two hydrogen atoms not forming a bridge; and
n signifies 0, 1, 2, 3 or 4;
as well as their pharmaceutically acceptable salts.
2. A compound of formula IA in accordance with claim 1,
Figure imgf000020_0002
wherein R and R are as defined in claim 1.
3. A compound of formula IB in accordance with claim 1,
Figure imgf000021_0001
wherein R and R are as defined in claim 1.
4. A compound of formula IC in accordance with claim 1,
Figure imgf000021_0002
wherein R1 and R2 are as defined in claim 1.
5. A compound of formula ID in accordance with claim 1,
Figure imgf000021_0003
wherein R1 and R are as defined in claim 1.
6. A compound of formula IE in accordance with claim 1,
Figure imgf000021_0004
wherein R and R are as defined in claim 1.
7. A compound of formula IA in accordance with claim 2, which is N-(2-methyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-ethyl-2H-tetrazol-5-yl)-2,2-diρhenyl-acetamide, N-(2-cyclopropylmethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-isopropyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide,
2,2-diphenyl-N-[2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl]-acetamide, 2,2-diphenyl-N-(2-propyl-2H-tetrazol-5-yl)-acetamide, N-(2-methoxymethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-tert-butyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-difluoromethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide, N-(2-cyanomethyl-2H-tetrazol-5-yl)-2,2-diphenyl-acetamide and (5-diphenylacetylamino-tetrazol-2-yl)-acetic acid methyl ester.
8. A compound of formula IB in accordance with claim 3, which compound is 9H-xanthene-9-carboxylic acid (2-methyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-cyclopropylmethyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-isopropyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid [2-(2,2,2-trifluoro-ethyl)-2H-tetrazol-5-yl] -amide, 9H-xanfhene-9-carboxylic acid (2-propyl-2H-tetrazol-5-yl)-amide,
9H-xanthene-9-carboxylic acid (2-methoxymethyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-tert-butyl-2H-tetrazol-5-yl)-amide, 9H-xanthene-9-carboxylic acid (2-difluoromethyl-2H-tetrazol-5-yl)-amide, 9H-xanfhene-9-carboxylic acid (2-cyanomethyl-2H-tetrazol-5-yl) -amide, {5-[(9H-xanthene-9-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester,
(RS)-l-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide, (RS)-2-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide and (RS)-4-methoxy-9H-xanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
9. A compound of formula IC in accordance with claim 4, which compound is
9H-thioxanthene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
10. A compound of formula ID in accordance with claim 5, which compound is 9,10-dihydro-anthracene-9-carboxylic acid (2-ethyl-2H-tetrazol-5-yl)-amide.
11. A compound of formula IE in accordance with claim 6, which compound is (RS)-6,l l-dihydro-dibenzo[b,e]oxepine-l l-carboxylic acid (2-efhyl-2H-tetrazol-5-yl)- amide.
12. A compound of formula IA, IB, IC, ID or IE, wherein R2 signifies hydrogen.
13. A medicament comprising a compound of formula I according to any one of claims 1-12 as well as pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
14. A medicament in accordance with claim 13 for the control or prevention of acute and/ or chronic neurological disorders such as restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest, hypoglycaemia, Alzheimer's disease, Huntington's chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, cognitive disorders, memory deficits, schizophrenia, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, acute and chronic pain, dyskinesia and depression.
15. The use of a compound of formula I in accordance with anyone of claims 1-12 as well as pharmaceutically acceptable salts thereof in the control or prevention of illnesses.
16. The use of compounds of formula I in accordance with anyone of claims 1-12 for the production of medicaments, containing a compound of formula I for the treatment of diseases relating to the mGlu receptor.
17. A compound of formula I in accordance with claims 1-12 as well as pharmaceutically acceptable salts thereof for the control or prevention of acute and/or chronic neurological disorders.
18. A process for the manufacture of compounds of formula I according to any one of claim 1-12 as well as of pharmaceutically acceptable salts thereof, which process comprises reacting a compound of formula
Figure imgf000023_0001
with a compound of formula
Figure imgf000024_0001
to a compound of formula
Figure imgf000024_0002
wherein the substituents have the significances set forth above, and, if desired, converting a functional group in a compound of formula I into another functional group and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
19. A compound in accordance with claims 1-12, when manufactured according to a process in accordance with claim 18.
20. The invention as herein described.
PCT/EP2001/007692 2000-07-13 2001-07-05 Tetrazole derivatives WO2002006254A1 (en)

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