USRE41425E1 - Piperazine and piperidine compounds - Google Patents
Piperazine and piperidine compounds Download PDFInfo
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- USRE41425E1 USRE41425E1 US12/081,710 US8171008A USRE41425E US RE41425 E1 USRE41425 E1 US RE41425E1 US 8171008 A US8171008 A US 8171008A US RE41425 E USRE41425 E US RE41425E
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- 0 *.CC.[1*]C.[3*]C1CC(C2=CC=CC=C2)CC([4*])N1C[5*] Chemical compound *.CC.[1*]C.[3*]C1CC(C2=CC=CC=C2)CC([4*])N1C[5*] 0.000 description 9
- QYAFFEOIFPAAHH-UHFFFAOYSA-N CC1=CC=CC2=C1OC=C2.CC1=CC=CC2=C1OCCCO2.CC1=CC=CC2=C1OCCO2.CC1=CC=CC2=C1OCCS2.[H]N1CCCC2=C1C=CC=C2C.[H]N1COC2=C1C=CC=C2C Chemical compound CC1=CC=CC2=C1OC=C2.CC1=CC=CC2=C1OCCCO2.CC1=CC=CC2=C1OCCO2.CC1=CC=CC2=C1OCCS2.[H]N1CCCC2=C1C=CC=C2C.[H]N1COC2=C1C=CC=C2C QYAFFEOIFPAAHH-UHFFFAOYSA-N 0.000 description 2
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- DVRAWFHFIRVNMQ-UHFFFAOYSA-N C1=CC(N2CCCCC2)=C2OC=CC2=C1.C1=CC(N2CCCCC2)=C2OCCOC2=C1.O=C1NC2=CC=CC(N3CCCCC3)=C2O1 Chemical compound C1=CC(N2CCCCC2)=C2OC=CC2=C1.C1=CC(N2CCCCC2)=C2OCCOC2=C1.O=C1NC2=CC=CC(N3CCCCC3)=C2O1 DVRAWFHFIRVNMQ-UHFFFAOYSA-N 0.000 description 1
- QETWPLSIFBAQOV-UHFFFAOYSA-N C1=CC=C(C2CCNCC2)C=C1.CC.CN1CCN(C2=CC=CC=C2)CC1 Chemical compound C1=CC=C(C2CCNCC2)C=C1.CC.CN1CCN(C2=CC=CC=C2)CC1 QETWPLSIFBAQOV-UHFFFAOYSA-N 0.000 description 1
- FFBJESQQEAJZQW-UHFFFAOYSA-N CC(=O)OCC1=CC=CC(C2=CC=CC=C2)=N1.CC1=CC=CC(C2=CC=CC=C2)=N1.CC1=CC=CC(C2=CC=CC=C2)=[N+]1[O-].ClC1=CC=CC(C2=CC=CC=C2)=N1.ClCC1=CC=CC(C2=CC=CC=C2)=N1.OCC1=CC=CC(C2=CC=CC=C2)=N1 Chemical compound CC(=O)OCC1=CC=CC(C2=CC=CC=C2)=N1.CC1=CC=CC(C2=CC=CC=C2)=N1.CC1=CC=CC(C2=CC=CC=C2)=[N+]1[O-].ClC1=CC=CC(C2=CC=CC=C2)=N1.ClCC1=CC=CC(C2=CC=CC=C2)=N1.OCC1=CC=CC(C2=CC=CC=C2)=N1 FFBJESQQEAJZQW-UHFFFAOYSA-N 0.000 description 1
- OSHNMVZYIGGFCR-UHFFFAOYSA-N CC1=CC=CC(C2=CC=C(F)C=C2)=N1.CC1=CC=CC(C2=CC=CC=C2)=N1.CC1=CC=NC(C2=CC=C(F)C=C2)=C1.CC1=CN=CC(C2=CC=C(F)C=C2)=C1.CC1=CN=CC(C2=CC=CC=C2)=C1.CC1=CN=CC(C2=CC=CS2)=C1.CC1=CN=CC(C2=COC=C2)=C1.CC1=CN=CC(C2=CSC=C2)=C1.CC1=NC=CC(C2=CC=C(F)C=C2)=C1 Chemical compound CC1=CC=CC(C2=CC=C(F)C=C2)=N1.CC1=CC=CC(C2=CC=CC=C2)=N1.CC1=CC=NC(C2=CC=C(F)C=C2)=C1.CC1=CN=CC(C2=CC=C(F)C=C2)=C1.CC1=CN=CC(C2=CC=CC=C2)=C1.CC1=CN=CC(C2=CC=CS2)=C1.CC1=CN=CC(C2=COC=C2)=C1.CC1=CN=CC(C2=CSC=C2)=C1.CC1=NC=CC(C2=CC=C(F)C=C2)=C1 OSHNMVZYIGGFCR-UHFFFAOYSA-N 0.000 description 1
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- MCTOKXVTAPJKIB-UHFFFAOYSA-N CCOC(=O)C1=CN=CC(Br)=C1.Cl.FC1=CC=C(C2=CC(CCl)=CN=C2)C=C1.O=C(O)C1=CN=CC(Br)=C1.OCC1=CN=CC(Br)=C1.OCC1=CN=CC(C2=CC=C(F)C=C2)=C1 Chemical compound CCOC(=O)C1=CN=CC(Br)=C1.Cl.FC1=CC=C(C2=CC(CCl)=CN=C2)C=C1.O=C(O)C1=CN=CC(Br)=C1.OCC1=CN=CC(Br)=C1.OCC1=CN=CC(C2=CC=C(F)C=C2)=C1 MCTOKXVTAPJKIB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- 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
- C07D405/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties.
- the inventors have discovered that compounds of the formula (a) wherein
- Preferred compounds according to the invention are the compounds of formula (a) wherein A together with the phenyl group represents a group of the formula b, c, d, e, f or g wherein n is 1 and R 1 and (R 2 )p, R 3 , R 4 , R 5 , (R 6 ) q , Y and Z have the above meanings, and the salts thereof.
- a together with the phenyl group represents the group of the formula (d), wherein R 1 , (R 2 ) p , R 3 and R 4 are hydrogen, n is 1, Z is nitrogen, and R 5 is the group 5-(4-fluorophenyl)-pyrid-3-yl, and the salts thereof.
- the compounds according to the invention show affinities for the dopamine D 2 receptor (pK i range 7-9.5) and dopamine D 4 receptor (pK i range 6.5-9.5) without significant preference for one of the above mentioned two receptors. Moreover, the compounds according to the invention show affinity for serotonin 5-HT 1A receptors (pK i range 7-9.5). This combination of affinities for dopamine and serotonin receptors is useful for the treatment of schizophrenia and other psychotic disorders and might allow for a more complete treatment of all disease symptoms, e.g., positive symptoms, negative symptoms and cognitive deficits.
- inventive compounds also show varying activities as either partial agonists or antagonists at dopamine D 2- , D 3- , and D 4- receptors. Some inventive compounds show agonist-like effects at dopamine receptors, however they potently antagonize apomorphine-induced climbing behavior in mice (ED 50 values ⁇ 1 mg/kg p.o). The inventive compounds further show varying activity as 5-HT 1A receptor agonists and induce aspects of the serotinin behavioral syndrome to differing intensities.
- inventive compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g., the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67, the disclosure of which is incorporated herein by reference), antidepressants (e.g., differential reinforcement of low rate responses; van Hest et al., Psychopharmacology, 1992, 107:474-479, the disclosure of which is incorporated herein by reference), and anxiolytics (e.g., suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97:147-148, the disclosure of which is incorporated herein by reference).
- antipsychotics e.g., the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67, the disclosure of which is incorporated herein by reference
- antidepressants e.g., differential reinforcement of low rate responses; van Hest et al
- the described compounds In contrast to clinically relevant dopamine D 2 receptor antagonists, the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents.
- the 5 -HT 1A receptor agonism inherent in the inventive compounds may be responsible for the reduced tendency to induce extrapyramidal effects and the therapeutic effects observed in behavioral models sensitive to either antidepressants or anxiolytics.
- inventive compounds are additionally expected to be of value for the treatment of affective disorders or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotinergic systems, for example: Parkinson's disease, aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, and in particular schizophrenia and other psychotic disorders.
- Parkinson's disease aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, and in particular schizophrenia and other psychotic disorders.
- Suitable acids with which the inventive compounds can form pharmaceutically acceptable acid addition salts are, for example, hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphtalene-sulphonic acid.
- the compounds of the invention can be brought into forms for administration by means of well known processes using auxiliary substances such as liquid and solid carrier materials.
- the compounds of the invention can be obtained according to methods (A and B) which are described below.
- the piperazines used in these methods are indicated as I-H to III-H, wherein I to III represent the following groups:
- a preferred method for preparing a compound of the formula (a) as defined above comprises either reacting a compound of formula with a compound of the formula R 5 —CH 2 —X, wherein X is a leaving group and the remaining substituents R 1 , R 2 , R 3 , R 4 , Z, A, p, n and R 5 are as defined above for formula (a), or reacting a compound of formula wherein R 5 ′ R′ 5 has the same meaning as R 5 given above in formula (a), with the proviso that the bromine atom is at the meta-position with respect to the methylene bridge, with a compound of the formula B(OH) 2 —Y, wherein B and Y have each substituent has the same meanings as given in formula (a) above.
- the resulting dark oil was purified by flash chromatography on silica gel (CH 2 Cl 2 /MeOH/NH 4 OH, 97.25 /2.5/0.25) to give A8 (0.9 g, 58%) as an oil.
- the product was converted to its monohydrochloride salt; the residue was dissolved in Et 2 O and treated with 1 eq. of ethanolic HCl. The product precipitated as a white solid.
- Step ii (scheme A2):
- Step iii (scheme A2):
- Step v (scheme A2):
- Q2-Cl was prepared analogously to the synthesis of Q1-Cl.
- Q3-Cl was prepared analogously to the synthesis of Q4-Cl (vide infra).
- Step ii (scheme A3):
- Step iii (scheme A3):
- Step ii (scheme A4):
- Step ii (scheme A5):
- Step iii (scheme A5):
- Step v (scheme A5):
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- Pharmacology & Pharmacy (AREA)
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- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
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- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
Abstract
A group of new piperazine and piperidine compounds having interesting advantageous pharmacological properties and have the formula (a)
wherein
wherein
-
- A represents a heterocyclic group having 5-7 ring atoms wherein 1-3 heteroatoms selected from the group O, N and S are present,
- R1 is hydrogen or fluoro,
- R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2,
- Z represents carbon or nitrogen, and the dotted line represents a single bond when Z is nitrogen, and represents a single or double bond when Z is carbon,
- R3 and R4 independently are hydrogen or C1-4-alkyl,
- n has the value 1 or 2,
- R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R6)q,
- Y is a phenyl, furanyl or thienyl group, which groups may be substituted with 1-3 substituents from the group hydroxy, halogen, CF3, C1-4-alkoxy, C1-4-alkyl, cyano aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl,
- R6 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3 and salts thereof, are disclosed.
Description
The invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties. The inventors have discovered that compounds of the formula (a)
wherein
wherein
-
- A represents a heterocyclic group having 5-7 ring atoms, wherein 1-3 heteroatoms selected from the group O, N and S are present,
- R1 is hydrogen or fluoro,
- R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2,
- Z represents carbon or nitrogen, and the dotted line represents a single bond when Z is nitrogen, and represents a single or double bond when Z is carbon,
- R3 and R4 independently are hydrogen or C1-4-alkyl,
- n has the value 1 or 2,
- R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R6)q,
- Y is a phenyl, furanyl or thienyl group, which groups may be substituted with 1-3 substituents selected from the group hydroxy, halogen, CF3, C1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl,
- R6 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3,
and the salts thereof have interesting and advantageous pharmacological properties.
Preferred compounds according to the invention are the compounds of formula (a) wherein A together with the phenyl group represents a group of the formula b, c, d, e, f or g
wherein n is 1 and R1 and (R2)p, R3, R4, R5, (R6)q, Y and Z have the above meanings, and the salts thereof.
wherein n is 1 and R1 and (R2)p, R3, R4, R5, (R6)q, Y and Z have the above meanings, and the salts thereof.
Particularly preferred are the inventive compounds of formula (a) wherein A together with the phenyl group represents a group of the formula (c) or (d), R5 has the above meaning and Y is phenyl which may be substituted as mentioned above, and wherein R2 has the above mentioned meaning, p=0 or 1, n is 1, R3 and R4 are hydrogen, R6 is hydroxy, methoxy or halogen, q is 0 or 1, Z is nitrogen, and the salts thereof.
Particularly preferred is the compound having formula (a) wherein A together with the phenyl group represents the group of the formula (d), wherein R1, (R2)p, R3 and R4 are hydrogen, n is 1, Z is nitrogen, and R5 is the group 5-(4-fluorophenyl)-pyrid-3-yl, and the salts thereof.
It is known from EP 0650964 that compounds of the formula
wherein R0 is C1-4-alkyl, which compounds can be substituted in the phenyl group and/or heterocyclic group and/or the piperazine group, act on the central nervous system by binding to 5-HT receptors. In particular these compounds bind to subtypes of the 5-HT-receptor, i.e. 5-HT1A and 5-HT1D receptors.
wherein R0 is C1-4-alkyl, which compounds can be substituted in the phenyl group and/or heterocyclic group and/or the piperazine group, act on the central nervous system by binding to 5-HT receptors. In particular these compounds bind to subtypes of the 5-HT-receptor, i.e. 5-HT1A and 5-HT1D receptors.
It has now surprisingly been found that the compounds according to the invention show affinities for the dopamine D2 receptor (pKi range 7-9.5) and dopamine D4 receptor (pKi range 6.5-9.5) without significant preference for one of the above mentioned two receptors. Moreover, the compounds according to the invention show affinity for serotonin 5-HT1A receptors (pKi range 7-9.5). This combination of affinities for dopamine and serotonin receptors is useful for the treatment of schizophrenia and other psychotic disorders and might allow for a more complete treatment of all disease symptoms, e.g., positive symptoms, negative symptoms and cognitive deficits.
The inventive compounds also show varying activities as either partial agonists or antagonists at dopamine D2-, D3-, and D4- receptors. Some inventive compounds show agonist-like effects at dopamine receptors, however they potently antagonize apomorphine-induced climbing behavior in mice (ED50 values<1 mg/kg p.o). The inventive compounds further show varying activity as 5-HT1A receptor agonists and induce aspects of the serotinin behavioral syndrome to differing intensities.
The inventive compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g., the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67, the disclosure of which is incorporated herein by reference), antidepressants (e.g., differential reinforcement of low rate responses; van Hest et al., Psychopharmacology, 1992, 107:474-479, the disclosure of which is incorporated herein by reference), and anxiolytics (e.g., suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97:147-148, the disclosure of which is incorporated herein by reference).
In contrast to clinically relevant dopamine D2 receptor antagonists, the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents.
The 5-HT1A receptor agonism inherent in the inventive compounds may be responsible for the reduced tendency to induce extrapyramidal effects and the therapeutic effects observed in behavioral models sensitive to either antidepressants or anxiolytics.
The inventive compounds are additionally expected to be of value for the treatment of affective disorders or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotinergic systems, for example: Parkinson's disease, aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, and in particular schizophrenia and other psychotic disorders.
Suitable acids with which the inventive compounds can form pharmaceutically acceptable acid addition salts are, for example, hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphtalene-sulphonic acid.
The compounds of the invention can be brought into forms for administration by means of well known processes using auxiliary substances such as liquid and solid carrier materials.
The compounds of the invention can be obtained according to methods (A and B) which are described below. The piperazines used in these methods are indicated as I-H to III-H, wherein I to III represent the following groups:
The synthesis of these piperazines I-H to II-H is described in EP 0189612, the disclosure of which is incorporated herein by reference.
The H-atom of the N—H moiety of compounds I-H to III-H can be replaced by group Q in two different chemical ways (A and B), eventually leading to the compounds of the invention. In FIG. 2, the meanings of Q1 to Q9 are shown.
Synthesis route A
Synthesis route A
The compounds listed in table A (vide infra) were prepared via the synthesis depicted in scheme A1 (vide infra): a piperazine was reacted with a compound Q—X (X═Cl, Br) in e.g., acetonitrile with Et(i-Pr)2N acting as a base; in some cases Kl (or Nal) be used instead of Et(i-Pr)2N.
Synthesis route B
Synthesis route B
The compounds listed in table B (vide infra) were prepared via the synthesis depicted in scheme Bi (vide infra): a piperazine was reacted with 3-bromo-5-chloromethylpyridine to yield the intermediate b1 (scheme B2), which was coupled with a boronic acid derivative by means of a so-called Suzuki cross-coupling reaction.
A preferred method for preparing a compound of the formula (a) as defined above, comprises either reacting a compound of formula
with a compound of the formula R5—CH2—X, wherein X is a leaving group and the remaining substituents R1, R2, R3, R4, Z, A, p, n and R5 are as defined above for formula (a), or reacting a compound of formula
wherein R5′ R′5 has the same meaning as R5 given above in formula (a), with the proviso that the bromine atom is at the meta-position with respect to the methylene bridge, with a compound of the formula B(OH)2—Y, wherein B and Y have each substituent has the same meanings as given in formula (a) above.
with a compound of the formula R5—CH2—X, wherein X is a leaving group and the remaining substituents R1, R2, R3, R4, Z, A, p, n and R5 are as defined above for formula (a), or reacting a compound of formula
wherein R5′ R′5 has the same meaning as R5 given above in formula (a), with the proviso that the bromine atom is at the meta-position with respect to the methylene bridge, with a compound of the formula B(OH)2—Y, wherein B and Y have each substituent has the same meanings as given in formula (a) above.
The preparation of the compounds of formula (a) and of a number of intermediate compounds will now be described in detail in the following nonlimiting
Procedure A1 (scheme A1):
To a suspension of 1-(2,3-dihydro-1,4-benzodioxin-5-yl) piperazine monohydrochloride III-H.HCl (1.1 g, 4.25 mmol) in CH3CN (40 ml) was added Q4-Cl (1.0 g, 3.87 mmol) and diisopropylethylamine (2.45 g, 19 mmol). The mixture was stirred at reflux for 3 hrs. After cooling and evaporation of the solvent in vacuo, the residue was taken up in CH2Cl2, washed with 5% NaHCO3 solution, saturated NaCl, dried (Na2SO4), filtered, and evaporated in vacuo. The resulting dark oil was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 97.25 /2.5/0.25) to give A8 (0.9 g, 58%) as an oil. The product was converted to its monohydrochloride salt; the residue was dissolved in Et2O and treated with 1 eq. of ethanolic HCl. The product precipitated as a white solid. The solid A8.HCl was collected by filtration and dried: mp 233-5° C., dec; 1H NMR (400 MHz, DMSO/CDCl3, 4/1) δ (ppm) 3.1-3.6 (cluster, 8H), 4.24 (m, 4H), 4.58 (s, 2H), 6.49 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.74 (t, 1H, J=8 Hz), 7.34 (m, 2H), 7.91 (m, 2H), 8.77 (m, 1H), 8.9 (m, 1H), 9.10 (m, 1H), 11.8 (br s, 1 H, NH+).
Procedure A1 (scheme A1):
A suspension of 2-(p-fluorophenyl)-4-bromomethylpyridine Q5-Br (0.71 g, 2.67 mmol), and 1-(2-benzoxazolinone-4-yl) piperazine I-H.HCl (0.58 g, 2.27 mmol) in DMF (20 ml) together with 2.1 equivalents of Et3N was stirred at room temperature for 2 h. The resulting clear solution was concentrated to give a red oil which was purified by flash column chromatography (SiO2, eluting with CH2Cl2/MeOH/NH4OH, 92/7.5/0.5) to give A9 (0.28 g, 26%) as a yellow solid: mp 213-4° C.; 1H NMR (400 MHz, DMSO/CDCl3, 4/1) δ (ppm) 2.62 (m, 4H), 3.24 (m, 4H), 3.64 (s, 2H), 6.59 (d, 1 H, J=8 Hz), 6.63 (d, 1H, J=8 Hz), 7.01 (t, 1H, J=8 Hz), 7.27 (m, 2H), 7.32 (m, 1H), 7.85 (m, 1H), 8.13 (m, 2H), 8.6 (m, 1H), 11.5 (s, 1H).
According to the syntheses given above, the other compounds A1-A12 were prepared in a similar way.
TABLE A | |||||||
melting point | |||||||
compound | piperazine | Q | X | salt | ° C. | ||
A1 | II | 1 | Cl | fb | 105-6 | ||
A2 | III | 1 | Cl | fb | 125-6 | ||
A3 | II | 2 | Cl | fb | 132-3 | ||
A4 | I | 2 | Cl | fb | 233-5 | ||
A5 | III | 3 | Cl | HCl | 208 | ||
A6 | I | 4 | Cl | fb | 214-5 | ||
A7 | I | 3 | Cl | fb | 172-3 | ||
A8 | III | 4 | Cl | HCl | 233-5 d | ||
A9 | I | 5 | Br | fb | 213-4 | ||
A10 | III | 5 | Br | 2HCl | 162 d | ||
A11 | III | 6 | Cl | 2HCl | 223 d | ||
A12 | I | 6 | Cl | 2HCl | 270-5 d | ||
fb = free base, | |||||||
d = decomposition |
Procedure B1 (scheme B1)
A solution of b1 (1.07 g, 2.75 mmol) and Pd(PPh3)4 (0.1 g, 0.08 mmol) in DME (5 ml) was stirred at room temperature for 10 minutes under a N2 atmosphere. Then 2-thiopheneboronic acid (0.39 g, 3.0 mmol) and an aqueous solution of Na2CO3 (2.75 ml of a 2M solution) were consecutively added and the mixture was allowed to react at reflux temperature for 1 hr. The solution was cooled, diluted with H2O, and extracted with CH2Cl2. The organic phase was evaporated to dryness in vacuo to give the crude product B1, which was purified by flash chromatography (CH2Cl2/MeOH, 98/2) and then converted to its monohydrochloride salt to obtain B1.HCl (0.8 g, 74%) as a white solid: mp 160° C., dec., material turned sticky; 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.0-3.8 (br b , 8H, NH+, H2O), 4.25 (m, 4H), 4.63 (br s, 2H), 6.54 (d, 1H, J=8 Hz), 6.64 (d, 1H, J=8 Hz), 6.75 (t, 1H, J=8 Hz), 7.14 (m, 1H), 7.43 (d, 1H, J=5 Hz), 7.74 (m, 1H).
According to the synthesis given above, the compounds B2-B3 were prepared in a similar way.
TABLE B | ||||
melting point | ||||
compound | piperazine | Q | salt | ° C. |
B1 | III | 7 | HCl | turns sticky |
at 160 | ||||
B2 | III | 8 | HCl | 224-5 |
B3 | III | 9 | HCl | 238-9 |
Intermediates used in route A
Intermediates Q—X:
Q1-Cl:
This step was carried out analogously to the procedure described in J. Het. Chem., 12, (1975), 443, the disclosure of which is incorporated herein by reference.
Step ii (scheme A2):
While stirring at room temperature, 4.8 g *28.5 mmol) of 2-phenyl-6-methyl-pyridine were dissolved in 50 ml of chloroform after which a solution of 7.8 g of 75% mCPBA (33.9 mmol) in 75 ml of chloroform were added dropwise. The reaction mixture showed only a slight rise in temperature. After stirring for 1.5 hr, the reaction mixture was shaken twice with 5% aqueous NaHCO3 solution and twice with an aqueous solution of Na2S2O3 to remove the excess of mCPBA, after which the reaction mixture proved to be negative on wet Kl/starch paper, The organic layer was dried on MgSO4. Removal of the drying agent by filtration and solvent by evaporation in vacuo yielded an oil which crystallized upon scratching to give 5.5 g (105%) of crude of 2-phenyl-6-methyl-pyridine-N-oxide, which was employed in the next step without further purification.
Step iii (scheme A2):
A stirred solution of the crude 2-phenyl-6-methyl-pyridine-N-oxide (5.2 g, 28.5 mmol) in Ac2O (25 ml) was heated at reflux temperature for 2 hrs. The Ac2O was removed with the aid of an oil pump (10 mm) at 40° C. to yield a red oil which was purified by flash chromatography over silica gel with Et2O/petroleum benzine=1/1 as the eluent and yielded 2-phenyl-6-(acetoxymethyl)-pyridine (4.6 g, 70%) as an oil.
Step iv (scheme A2:)
4.5 g of 2-phenyl-6-(acetoxymethyl)-pyridine (20 mmol) was treated with an aqueous HCl solution (15%, 10 ml) and the mixture was heated at reflux temperature while stirring. After 30 minutes the reaction mixture was concentrated with the aid of an oil pump (10 mm) at 40° C., CH3CN was added, and the mixture was evaporated to dryness in vacuo and yielded 2-phenyl-6-(hydroxymethyl)-pyridine (3.0 g, 80%) as an oil.
Step v (scheme A2):
To a stirred solution of 2-phenyl-6-(hydroxymethyl)-pyridine (1.0 g, 5.4 mmol) in CHCl3 (7 ml) at room temperature was added dropwise SOCl2 (1.22 g, 10.2 mmol) and the mixture was heated at 60° C. for 20 minutes. After evaporation of the solvent in vacuo, the residue was purified by trituration with Et2O. The resulting precipitate was collected by filtrition and dried to give 2-phenyl-6-(chloromethyl)-pyridinium chloride Q1-Cl (1.2 g, 92%) as a white solid.
Q2-Cl:
Q2-Cl was prepared analogously to the synthesis of Q1-Cl.
Q3-Cl
Q3-Cl was prepared analogously to the synthesis of Q4-Cl (vide infra).
Q4-Cl:
A stirred mixture of 3-bromo-5-pyridine-carboxylic acid (10.1 g, 50 mmol) and H2SO4 (1.5 ml) in EtOH (150 ml) was refluxed for 6 hrs. After cooling, the solvent was removed by evaporation in vacuo. The residue as diluted with H2O (100 ml), basified with 5% NaHCO3 (aq) solution and extracted with ether (4×100 ml). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4. Filtration and concentration in vacuo of the filtrate yielded 3-bromo-5-pyridine-carboxylic acid ethyl ester as an oil that solidified on standing: (9.8 g, 85%).
Step ii (scheme A3):
To a stirred solution of 3-bromo-5-pyridine-carboxylic acid ethyl ester (9.5 g, 41.3 mmol) in EtOH (96%, 220 ml), NaBH4 (14.4 g, 380 mmol) was added slowly at 25° C.
The reaction was mildly endothermic. The mixture was stirred under an nitrogen atmosphere at room temperature for 6 hrs. The resulting milky mixture was diluted with H2O (150 ml), the EtOH was evaporated in vacuo and the residue was extracted with CH2Cl2 (3×). The combined organic layers were dried on Na2SO4. After filtration the filtrate was concentrated in vacuo to give 9 g of a crude oil which was purified by flash chromatography on silica gel (eluent: Et2O) to give 3-bromo-5-hydroxymethyl-pyridine (3.5 g, 45%).
Step iii (scheme A3):
To a solution of 3-bromo-5-hydroxymethyl-pyridine (3.3 g, 17.5 mmol) in toluene (35 ml) was added Pd(PPh3)4 (0.6 g, 0.52 mmol), an aqueous solution of Na2CO3 (17.5 ml of a 2M solution) and p-fluorphenylboronic acid (2.65 g, 19 mmol, dissolved in 8.5 ml EtOH). The mixture was heated at 80-90° C. for 1 hr and vigorously stirred. After the reaction was completed, the biphasic reaction mixture was cooled, the organic layer was collected and washed with saturated NaCl. The aqueous layer was washed with EtOAc and the combined organic layers were dried on Na2SO4. The drying agent was removed by filtration and the solvent was evaporated in vacuo to give a dark oil which was purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH, 95/4.5/0.5) and yielded 3-(p-fluorophenyl)-5-hydroxymethyl-pyridine (3.0 g, 84%). The product was converted into its monohydrochloride salt; the residue was dissolved in Et2O and treated with 16.5 eq of ethanolic HCl. The product 3-(p-fluorophenyl)-5-hydroxymethyl-pyridinium hydrochloride Q4-OH.HCl precipitated as a white solid which was collected by filtration and subsequent drying.
Step iv (scheme A3):
3-(p-fluorophenyl)-5-hydroxymethyl-pyridinium hydrochloride Q4-OH.HCl (3.5 g, 14.7 mmol) was added to an excess of SOCl2 (20 ml) and the mixture was heated at 60° C. to start the reaction (generation of HCl). After complete conversion of the starting material (45 min), the reaction mixture was cooled and excess SOCl2 was removed in vacuo to leave a dry residue. Crystallization from Et2O provided 3-(p-fluorophenyl)-5-chloromethyl-pyridinium hydrochloride Q4-Cl.HCl (2.5 g, 66%).
Q5-Br:
A solution of 2-bromo-4-methyl-pyridine (10 g, 58 mmol) and Pd(PPh3)4 (1.5 g, 1.3 mmol) in toluene (110 ml) was stirred at room temperature under a nitrogen atmosphere. Subsequently an aqueous solution of Na2 CO3 (58 ml of a 2M solution) and p-fluorophenylboronic acid (8.93 g, 63.8 mmol) were added and the resulting mixture was allowed to react at 90-100° C. for 4 hrs. The mixture was cooled, the aqueous layer was separated and extracted with EtOAc (2×). The combined EtOAc and toluene fractions were dried on MgSO4. Filtration of the drying agent and removal of the solvent in vacuo yielded a pink oil (28 g). Distillation gave pure 2-(p-fluorophenyl)-4-methyl-pyridine (6.10 g, 56%); bp 110-116° C. (6-7 mbar) as a colorless oil.
Step ii (scheme A4):
A mixture of 2-(p-fluorophenyl)-4-methyl-pyridine (0.5 g, 2.67 mmol), N-bromosuccinimide (0.48 g, 2.69 mmol), and a catalytic amount of benzoylperoxide in CCl4 (50 ml) was stirred at reflux temperature and irradiated by means of an ordinary 250-W UV lamp for 4 hrs. Afterwards, the reaction mixture was cooled and subsequently triturated with Et2O/petroleum benzine. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give 2-(p-fluorophenyl)-4-bromomethyl-pyridine (0.63 g, 88%, unstable) as a dark yellow oil.
Q6-Cl:
The intermediate Q6-Cl was synthesized according to the scheme given below (scheme A5):
Step i (scheme A5):
Step i (scheme A5):
4-(p-fluorophenyl)pyridine (13 g, 75 mmol) was dissolved in glacial acetic acid (100%; 50 ml) at 70-80° C. Subsequently H2O2 (35%; 8 ml) was added while stirring. After 4 hrs an additional portion of H2O2 (35%; 5 ml) was added. The reaction mixture was allowed to cool after which it was evaporated to dryness in vacuo leaving a yellow solid which was diluted with H2O (150 ml), basified with an aqueous solution of NaOH (150 ml of a 2M solution), and extracted with CH2Cl2 (100 ml). The organic layer was separated and dried on Na2SO4. After removal of the drying agent by filtration and evaporation of the solvent in vacuo, 13 g (91%) of the desired product 4-(p-fluorophenyl)pyridine-N-oxide were isolated.
Step ii (scheme A5):
To 13 g of 4-(p-fluorophenyl)pyridine-N-oxide (68.7 mmol) was added Me2SO4 (8.6 g, 68 mmol) at 80° C. under an N2 atmosphere after which the mixture was stirred a 100-110° C. for 2 hrs. The mixture was cooled and 70% dioxan/water was poured into the reaction mixture. The obtained dark brown solution was added dropwise to a stirred solution of NaCN (10 g, 0.20 mol) in H2O (85 ml) at 15-20° C. The mixture was stirred at room temperature for 3 hrs. The reaction mixture was filtered, the residue was washed with CH2Cl2, which was added to the biphasic filtrate. The organic layer of the filtrate was dried on Na2SO4. Removal of the drying agent by filtration and evaporation of the solvent in vacuo, yielded the desired compound as a light brown solid which was purified by crystallization from EtOH (300 ml) to provide 2-cyano-4-(p-fluorophenyl)pyridine (8.6 g, 68%): mp 194-195° C.
Step iii (scheme A5):
A stirred solution of 2-cyano-4-(p-fluorophenyl)pyridine (8.6 g, 46.7 mmol) in saturated HCl-MeOH (200 ml) was allowed to react at reflux temperature for 6 hrs. The resulting pink solution was concentrated in vacuo to a volume of approximately 50 ml, after which it was diluted with 250 ml of water. The latter solution was basified with an aqueous solution of NH4OH (25%), and extracted with CH2Cl2. The organic layer was dried on Na2SO4. Removal of the drying agent by filtration and evaporation of the solvent in vacuo, yielded the desired product 4-(p-fluorophenyl)pyridine-2-carboxylic acid methyl ester as a pink solid (5.0 g, 46%): mp 97-8° C.
Step iv (scheme A5):
NaBH4 (8.2 g, 0.2 mol) was added portionwise to a stirred solution of 4-(p-fluorophenyl)pyridine-2-carboxylic acid methyl ester (5.0 g, 21.6 mmol) in EtOH (96%, 100 ml) and the mixture was stirred at room temperature for 6 hrs. The solvent was removed at reduced pressure after which water was added. Subsequently extraction with EtOAc took place. The organic layer was dried on MgSO4. Removal of the drying agent and evaporation of the solvent in vacuo yielded an oil which was dissolved in MeOH and treated with 1.1 eq. HCl/EtOH to afford 2-hydroxymethyl-4-(p-fluorophenyl)pyridinium hydrochloride Q6-OH.HCl as a yellow foam (4.47 g, 87%).
Step v (scheme A5):
This reaction was performed analogously to step iv in scheme A3.
Intermediates used in route B.
Intermediate b1:
To a suspension of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine monohydrochloride (5.4g, 21 mmol) in CH3CN (125 mmol) was added 3-bromo-5-chloromethyl-pyridine (4.6 g, 19 mmol) and diisopropylethylamine (12.3 g, 95 mmol). The mixture was stirred at reflux temperature for 30 min. After cooling of the mixture and evaporation of the solvent in vacuo, the residue was taken up in (CH2Cl2, washed with 5% NaHCO3 (aq) solution, saturated NaCl (aq) solution after which the organic fraction was dried on Na2SO4. After removal of the drying agent by filtration and solvent by evaporation in vacuo, the residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 97.25/2.5/0.25) to give b1 (7.2 g, 97%) as an oil.
Claims (12)
wherein
A represents a heterocyclic group having 5-7 ring atoms wherein 1-3 heteroatoms selected from the group O, N and S are present,
R1 is hydrogen or fluoro,
R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2,
Z represents carbon or nitrogen, and the dotted line represents a single bond when Z is nitrogen, and represents a single or double bond when Z is carbon,
R3 and R4 independently are hydrogen or C1-4-alkyl, n has the value 1 or 2,
R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R6)q,
Y is a phenyl, furanyl or thienyl group, which groups may be substituted with 1-3 substituents selected from the group hydroxy, halogen, CF3, C1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl,
R6 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 , wherein A together with the phenyl group represents a group of the formula (c) or (d), wherein R5 has the meaning given in claim 1 , Y is phenyl, R3 and R4 are hydrogen, R6 is hydroxy, methoxy or halogen, q is 0 or 1 and Z is nitrogen, or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 3 , wherein A together with the phenyl group represents a group of the formula (d), wherein R1, (R2)p, R3 and R4 are hydrogen, p is 0, n is 1, Z is nitrogen, and R5 is the group 5-(4-fluorophenyl)-pyrid-3-yl, or a pharmaceutically acceptable salt thereof.
5. A method for preparing a compound of the formula (a) according to claim 1 , said method comprising
with a compound of the formula R5—CH2—X, wherein X is a leaving group; or
wherein R5′ has the same meaning as R5 as given in claim 1 , with the proviso that the bromine atom is at the meta-position with respect to the methylene bridge R′5 is 2 -pyridyl, 3 -pyridyl or 4 -pyridyl substituted at the meta-position with respect to the methylene bridge with the bromine atom, with a compound of the formula B(OH)2—Y, in which each substituent has the meanings given in claim 1 .
6. A pharmaceutical composition, said composition comprising a pharmaceutically effective amount of at least one compound according to claim 1 and a pharmaceutically acceptable carrier.
7. A method of preparing a pharmaceutical composition for treating a CNS disorder, said method comprising including in adding to said composition a pharmaceutically effective amount of at least one compound of the formula (a) according to claim 1 and a pharmaceutically acceptable carrier.
8. A method of treating a CNS disorder, said method comprising administering to a host in need of said treatment an effective amount of a compound of formula (a) according to claim 1 .
wherein R1, (R2)p, Z, n, R3 and R4 have the meanings given in claim 1 , and R5′ has the same meaning as R5 given in claim 1 , with the proviso that the bromine atom is at the meta-position with respect to the methylene bridge R′5 is 2 -pyridyl, 3 -pyridyl or 4 -pyridyl substituted at the meta-position with respect to the methylene bridge with the bromine atom.
10. A pharmaceutical composition, said composition comprising a pharmaceutically effective amount of at least one compound according to claim 4 and a pharmaceutically acceptable carrier.
11. A method of preparing a pharmaceutical composition for treating a CNS disorder, said method comprising adding to said composition a pharmaceutically effective amount of at least one compound according to claim 4 and a pharmaceutically acceptable carrier.
12. A method of treating a CNS disorder, said method comprising administering to a host in need of said treatment an effective amount of at least one compound according to claim 4 .
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