ZA200601173B - Trans-1(6-Chloro-3-Phenylindan-1-YL)-3,3 Dimenthylpiperazine - Google Patents
Trans-1(6-Chloro-3-Phenylindan-1-YL)-3,3 Dimenthylpiperazine Download PDFInfo
- Publication number
- ZA200601173B ZA200601173B ZA200601173A ZA200601173A ZA200601173B ZA 200601173 B ZA200601173 B ZA 200601173B ZA 200601173 A ZA200601173 A ZA 200601173A ZA 200601173 A ZA200601173 A ZA 200601173A ZA 200601173 B ZA200601173 B ZA 200601173B
- Authority
- ZA
- South Africa
- Prior art keywords
- compound
- salt
- disorder
- symptoms
- abuse
- Prior art date
Links
- CVGKRXPEFQXHPJ-WYEAGLDESA-N ClC1=CC=C2[C@@H](C[C@H](C2=C1)N1CC(NCC1)(C1CC(CCC1C(C)C)C)C1CC(CCC1C(C)C)C)C1=CC=CC=C1 Chemical compound ClC1=CC=C2[C@@H](C[C@H](C2=C1)N1CC(NCC1)(C1CC(CCC1C(C)C)C)C1CC(CCC1C(C)C)C)C1=CC=CC=C1 CVGKRXPEFQXHPJ-WYEAGLDESA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- 208000028017 Psychotic disease Diseases 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 22
- 201000000980 schizophrenia Diseases 0.000 claims description 22
- 208000024891 symptom Diseases 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 208000007848 Alcoholism Diseases 0.000 claims description 8
- 206010001584 alcohol abuse Diseases 0.000 claims description 8
- 208000025746 alcohol use disease Diseases 0.000 claims description 8
- 208000020925 Bipolar disease Diseases 0.000 claims description 7
- 208000022497 Cocaine-Related disease Diseases 0.000 claims description 7
- 206010013654 Drug abuse Diseases 0.000 claims description 7
- 206010026749 Mania Diseases 0.000 claims description 7
- 208000027089 Parkinsonian disease Diseases 0.000 claims description 7
- 206010034010 Parkinsonism Diseases 0.000 claims description 7
- 201000001272 cocaine abuse Diseases 0.000 claims description 7
- 201000009032 substance abuse Diseases 0.000 claims description 7
- 208000021465 Brief psychotic disease Diseases 0.000 claims description 6
- 208000024254 Delusional disease Diseases 0.000 claims description 6
- 208000019695 Migraine disease Diseases 0.000 claims description 6
- 208000020186 Schizophreniform disease Diseases 0.000 claims description 6
- 206010043903 Tobacco abuse Diseases 0.000 claims description 6
- 206010027599 migraine Diseases 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 208000002851 paranoid schizophrenia Diseases 0.000 claims description 6
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 206010054089 Depressive symptom Diseases 0.000 claims description 5
- 208000019022 Mood disease Diseases 0.000 claims description 5
- 208000019568 Shared Paranoid disease Diseases 0.000 claims description 5
- 208000028810 Shared psychotic disease Diseases 0.000 claims description 5
- 239000012971 dimethylpiperazine Substances 0.000 claims description 5
- 208000019116 sleep disease Diseases 0.000 claims description 5
- 208000022610 schizoaffective disease Diseases 0.000 claims description 4
- 208000022925 sleep disturbance Diseases 0.000 claims description 4
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 2
- 229960002715 nicotine Drugs 0.000 claims description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 2
- PIPWSBOFSUJCCO-UHFFFAOYSA-N 2,2-dimethylpiperazine Chemical compound CC1(C)CNCCN1 PIPWSBOFSUJCCO-UHFFFAOYSA-N 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000000945 filler Substances 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical group OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 230000003001 depressive effect Effects 0.000 claims 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- -1 phenylmethoxycarbonyl Chemical group 0.000 claims 1
- 230000000630 rising effect Effects 0.000 claims 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 16
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 14
- 229940079593 drug Drugs 0.000 description 10
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 8
- 229960003638 dopamine Drugs 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000003176 neuroleptic agent Substances 0.000 description 4
- 230000000701 neuroleptic effect Effects 0.000 description 4
- 208000018452 Torsade de pointes Diseases 0.000 description 3
- 208000002363 Torsades de Pointes Diseases 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 239000000164 antipsychotic agent Substances 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 108060003345 Adrenergic Receptor Proteins 0.000 description 2
- 102000017910 Adrenergic receptor Human genes 0.000 description 2
- 108090000511 Dopamine D1 Receptors Proteins 0.000 description 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000000561 anti-psychotic effect Effects 0.000 description 2
- 229940005529 antipsychotics Drugs 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000000698 schizophrenic effect Effects 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- FBCSWIXKXHSYBN-AZUAARDMSA-N 1-[(1r,3s)-6-chloro-3-phenyl-2,3-dihydro-1h-inden-1-yl]-3,3-dimethylpiperazine Chemical compound C1CNC(C)(C)CN1[C@H]1C2=CC(Cl)=CC=C2[C@H](C=2C=CC=CC=2)C1 FBCSWIXKXHSYBN-AZUAARDMSA-N 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000007220 Cytochrome P-450 CYP2D6 Inhibitors Diseases 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 102000004076 Dopamine D1 Receptors Human genes 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101150104779 HTR2A gene Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 230000003379 hyperdopaminergic effect Effects 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002468 indanes Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 229940054010 other antipsychotics in atc Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 229960002195 perazine Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
TRANS-1-(6-CIILORO-3-PHENYLINDAN-1-YL)-33-DIMETHYLPIPERA ZINE
The present invention relates to trans-1-(6-chloro-3-phenylindamn-1-y1)-3,3- dimethylpiperazzine and salts thereof, in particular for medical use, including for treatment of schizophrenia oer other diseases involving psychotic symptoms.
Background o-f the Invention
The compound, which is the subject of the present invention (Compound I trans-1- ((IR, 35)-6-chloro-3-phenylindan-1-y1)-3,3-dimethylpiperazine) has the general feormula (D).
H
/
Re
N
Cl. 3
U)
A group of co-mpounds structurally related to Compound I, i.e. trans isomers of 3-aryl-1-(1- piperazinyl)indanes substituted in the 2- and/or 3-position of the piperazine ring, has been described in =P 638 073; Boges et al. in J. Med. Chem., 1995, 38, 4380-4392 and Klaus P.
Bogese in "Derug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phemylindans and
Related Comppounds", 1998, ISBN 87-88085-10-41. These compounds are described as having high a—ffinity for dopamine (DA) D, and D; receptors and the 5-HT, recseptor and are suggested to be useful for treatment of several diseases in the central nervous system, including schi_zophrenia.
An enantiome=r corresponding to the compound of the formula (I) but differing in that it has a methyl group instead of a hydrogen on the piperazine has been disclosed in Bogesa et al. in J. Med. Chem., 1995, 38, 4380-4392, see table 5, compound (-)-38. This publication concludes that the (-)-enantiomers of compound 38 is a potent D;/D; antagonists showing some Dj selectivity in vitro while in vivo it is equipotent as Dj and D, artagonist. The compound is described as a poterat 5-HT» antagonist, having high affinity for oy adrenoceptors. : ‘
None of the above references discloses the specific enantiomeric form above (Compeound I) or the medical use thereof. The trans Jsomer in the form of the racemate of Compound 1 is only indirectly disclosed as an intermediate in the synthesis of compound 38 in Bogessa et al. in J. Med. Chem., 1995, 38, 4380-4392) while the medical use of Compound I oer of its corresponding racemate is not described.
The aetiology of schizophrenia is not Jknown, but the dopamine hypothesis of schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173), formulated in the early 1960s, hass provided a theoretical framework for winderstanding the biological mechanisms underlying this disorder. In its simplest form, the dopamine hypothesis states that schizophrenia is associated with a hyperdopaminergic state, a notion which is supported by the fact thmat all antipsychotic drugs on the market tod ay exert some dopamine D; receptor antagonism (Seeman Science and Medicine 1995, 2, 28-37). However, whereas it is generally acecepted that antagonism of dopamine D; receptors in the limbic regions of the brain plays a key role in the treatment of positive symptoms of schizophrenia, the blockade of D, receptorss in striatal regions of the brain causes ex#rapyramidal symptoms (EPS). As described in EP 638 073 a profile of mixed dopamine D;/ID; receptor inhibition has been observed with ssome so- called "atypical" antipsychotic compounds, in particular with clozapine, used in trea—tment of schizophrenic patients. Central a; antagonistic actions has also been suggested to contribute in improving antipsychotic properties (Millan et al, JPET, 2000, 292, 38-53).
Further, selective D, antagonists haves been connected to treatment of sleep disorder sand alcohol abuse (D.N.Eder, Current Opinion in Investigational Drugs, 2002 3(2) :284—288).
Dopamine may also play an importarat role in the etiology of affective disorders (P. “Willner,
Brain. Res. Rev. 1983, 6, 211-224, 2225-236 and 237-246; J. Med. Chem. 1985, 28, M817- 1828).
In EP 638 073 is described how compounds having affinity for 5-HT; receptors, in gparticular 5-HT; receptors antagonists, have be en suggested for treatment of different diseasess, such as schizophreniza including the negative symptoms in schizophrenic patients, depression, anxiety, sleep disturbance, migraine attacks and neuroleptic-induced parki-nsonism. 5-HT> receptor antagonism has also been suggested to reduce the incidence of extrapyramidal side effects induc-ed by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67- 69).
The products of the invention and the medical use thereof
The inventors have found that Compound I displays high affinity for dopamine D1 receptors, dopamine D2 receptors and for alfal adrenoceptors. Furthermore, compound 1 has been found to be an antagonist at dopamine D1 and D2 receptors, and at serotonin 5-HT2a receptors. The pharmacological activities of compound I are with respect to these receptors found to be similar to that of the compound described above differirag structurally from
Compound I in that it has a methyl group instead of a hydrogen on the pi—perazine.
The inventeors have also found that several of the structurally "relate=d compounds, both racemates sand enantiomers, described in the above mentioned references are CYP2D6 (Cytochrome P450 2D6) inhibitors whereas Compound I is a relative®y weak inhibitor of
CYP2D6, also in comparison with other antipsychotics such ass Haloperidole and
Risperidone=. The racemate of the compound of the present invention is also considerable more potenst on the CYP2D6 enzyme compared to the enantiomer of tine present invention, i.e. Compownd IL
The CYP2ID6 enzyme is a liver enzyme important for metabolism. CYP 2D6 is a mammalian enzyme cosmmonly associated with the metabolism of pharmaceutical compounds and inhibition cof this drug metabolizing enzyme may lead to clinically significant drug-drug interactions i.e. if two drugs are given in combination and are metabolised by the same enzymes, c-ompetition for metabolism may give rise to increased plasmma concentrations and therefore possible adverse effects (for review see Lin et al, Pharmacological Rev. 1997, 49, 403-449, B-ertz RJ and Granneman GR. Clin Pharmacokinet 1997, 32, 210-258).
Since more than 80 drugs in clinical use (and in particulasr psychotropic drugs) are metabolized boy CYP2D6 (Bertz RJ, Granneman GR. Clin Pharamacokin 1997, 32, 210-58,
Rendic S, DiCarlo FJ. Drug Metab Rev 1997, 29, 413-580), in hibition of this enzyme by coadministereed drugs can lead to dramatic increases in exposure Jevels and resulting toxicity as seen with the combination of the well known CYP2D6 inhibit-ors fluoxetine or paroxetine in combination with Imipramine, Desimipramine or Nortriptyline, resulting in increased cadiac toxicitsy of these tricyclics (Ereshefsky L. el al. J. Clin. Psychiatry 1996, 57(suppl8), 17-25, Shulmzan RW Can J Psychiatry, Vol 42, Supplement 1, 453).
The fact that @ompound I has a low interaction with the liver enszyme CYP2D6 means that it has a reduced potential for drug to drug interaction, i.e. there i s possibly less drug to drug interaction when a patient is treated with the compound of thes present invention together with other Mrugs which are mainly metabolised by the C™YP2D6 enzyme. This is a considerable advantage, in particular for patients with schizophrenia which are often treated with other medicaments to control their disease.
The inventors have also found that Compound I has a relatively low prolonging effect on the
QT-interval iin the electrocardiogram (ECG) of the "alpha~chleoraose anaesthetised rabbit". Drug-inducecd QT-interval prolongation in the electrocardiograrm (ECG) and the appearance of fatal cardi ac arrhythmias, torsade de pointes (TdP), has become recognised as a potential risk during treatment with a broad range of drugs inclu ding repolarisation-delaying antiarrhythm-ics [C.L. Raehl, AK. Patel and M. LeRoy, Clin Pharm 4 (1985), 675-690}, various antibyistamines [R.L. Woosley, Annu Rev Pharmacol “I oxicol 36 (1996), 233-252; ] 25 Y.G. Yap amd A.J. Camm, Clin Exp Allergy 29 Suppl 1 (19999), 15-24], antipsychotics [A.H. Glassaman and J.T. Bigger, Am J Psychiatry 158 (2%001), 1774-1782] and anti- microbial agents [B. Darpd, Bur Heart J 3 Suppl K (2001), K70-K80). The fact that
Compound I has a relatively low effect on the rabbit QT interval means that this compound has a reduced potential for introducing drug-induced QT interval prolongation and appearance of fatal cardiac arrhythmias, torsade de pointes (L"dP), in humans compared to several comrmercialised antipsychotics.
Thus, in one aspect, the invention relates to the compound of formul al (Compound I) and salts thereof. The salt of the invention, i.e. of the compound of forrmula (I), may, e.g. be selected from a —fumarate or a maleate salt of Compound L
T
)
N
«Cl ) { : } g o
The properties of Compound I indicate that it will be particularly useful as a pharmaceutical.
Accordingly, fhe present invention further relates to a pharmac-eutical composition of
Compound I o=f the invention or a salt thereof. The invention also re=lates to the medical use of such compounds, salts and compositions, such as for the treatment of a disease in the central nervou_s system, including psychosis, in particular schizophrenia or other diseases involving psychotic symptoms, such as, e.g, Schizophrenia, Schi_zophreniform Disorder,
Schizoaffectivee Disorder, Delusional Disorder, Brief Psychotic Dis-order, Shared Psychotic
Disorder as well other psychotic disorders or diseases that present with psychotic symptoms, e.g mania in bipolar disorder.
Additionally, €he 5-HT, antagonistic activity of the compound of the= invention suggests that the compound. or salt thereof may have a relatively low risk of extrapyramidal side effects.
The present inavention also relates to use of Compound I of the inveration, or a salt thereof for treatment of aa disease selected from the group consisting of anxxiety disorders, affective disorders including depression, sleep disturbances, migraire, neuroleptic-induced parkinsonism. cocaine abuse, nicotine abuse, alcohol abuse and othesr abuse disorders.
In a preferred embodiment, the present invention relates to a method of treating
SchizophrenifSorm Disorder, Schizoaffective Disorder, Delusional IDisorder, Brief Psychotic
Disorder, Shared Psychotic Disorder or mania in bipolar dAsorder, comprising administering a therapeutically effective amount of Compound I of the in-vention or a salt thereof.
A further embodiment of the invention relates to a method of treating positive symptoms of s schizoplarenia comprising administering a therapeutically effective amount of Compound 1 ora salt thereof.
Another~ embodiment of the invention relates to a method of treating negative symptoms of schizophrenia comprising administering a therapeutically effective amount of the
Compowand I or a salt thereof.
A furtheer embodiment of the invention relates to a method of treating depressive symptoms of schizophrenia comprising administering a therapeuticanlly effective amount of Compound
I or a salt thereof.
A furthuer aspect of the invention relates to a method of treating mania and/or maintenance of bipolar disorder comprising administering a therapeuticak ly effective amount of Compound I or a sal_t thereof.
A further aspect of the invention relates to a method of treating neuroleptic-induced parkinssonism comprising administering a therapeutically effective amount of the Compound lIoras alt thereof.
The in—vention further relates to a method of treating sulostance abuse, e.g. nicotine, alcohol or cocaine abuse, comprising administering a therapeutically effective amount of Compound
I or a ssalt thereof.
In a broad aspect, the present invention relates to trans- 1 -(6-chloro-3-phenylindan-1-y1)-3,3- dimetaylpiperazine or a salt thereof for use as a medicament.
Accoredingly, the present invention also relates to a method of treating a disease selected from the group consisting of a disease involving psychotic symptoms, schizophrenia (e.g.
one or more of positives symptoms, negative sympstoms and depressive symptoms of schizophrenia), Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder,
Brief Psychotic Disorder, Shared Psychotic Disorder, and mania in bipolar disorder, anxiety disorders, affective disorders including depression, sleep disturbances, migraine, neuroleptic-induced parkinsonism, and abuse disorders, ¢.g. cocaine abuse, nicotine abuse, or alcohol abuse, comprising administering a therapeutically effective amount of the compound trans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine or a salt thereof.
As used herein the term "frans-1-(6-chloro-3-phenylinclan-1-y1)-3,3 -dimethylpiperazine", i.e. without any specific indication of the enantiomer forrm (e.g. using (+) and (=), or using the
R/S-convention, is meant to refer to any enantiomeric- form of this compound, i.e. either of the two enantiomers or to a mixture of the two, e.g. the racemic mixture). However, in this context preferably the content of the enantiomer corresponding to that of Compound I is at least 50%, i.e. at least as the racemic mixture, but preferably Compound L is in enantiomeric excess.
In the present context for the pharmaceutical uses it i.s understood that when specifying the enantiomer form as done in formula (I) for Compound 1, then the compound is relatively stereochemically pure, preferably the enantiomeric excess is of at least 70%, and more preferably at least 80% (80% enantiomeric excess me=ans that the ratio of I to its enantiomer is 90:10 in the mixture in question) at least 90%, at le=ast 96%, or preferably at least 98%. In a preferred embodiment, the diastereomeric excess -of Compound I is at least 90% (90% diastereomeric purity means the ratio of Comp-ound I to cis-1-((1S,35)-6-chloro-3- phenylindan-1-y1)-3,3-dimethylpiperazine is 95:5), at least 95%, at least 97%, or at least 98%.
A further aspect of the invention relates to a method of treatment as described herein, wherein the patient treated with Compound I or a salt: thereof is also treated with at least one other medicament. A particular relevant embodimerat in this connection, is treatment with other medicaments being metabolised by CYP2D6.
Claims (38)
1. A compound of formula (Compound I, trans-1-((1R,3S)-6-chloro-3- phaenylindan-1-yl)-3,3-dimethylpiperazine) H / T* J
Cl. 3 D or a salt thereof.
2. The compound or salt of claim 1 being substantCially pure.
3. A pharmaceutical composition comprising the compound or salt of claim 1 or 2 together with at least one pharmaceutically acceptable carrier, filler or diluent.
4. The pharmaceutical composition according to claim 3 wherein the emxantiomeric excess of Compound I is at leastc 90%, at least 96%, or at least
98%.
5. A compound or salt of claim 1 or 2 for use in maedicine.
6. Usse of a compound or salt of claim 1 or 2 in tke preparation of a medicament fo the treatment of a disease selected from th e group consisting of a disease involving psychotic symptoms, schizophrenia, anxiety disorders, affective disorders including depression, sleep disturtoances, migraine, neuroleptic- induced parkinsonism, abuse disorders, cocaine abuse, nicotine abuse, and alcohol abuse. Amended sheet 2/04/2007
7. Use of claim 6 in the preparation of a medicament for the treatment of schizophrenia or other psychotic disorders.
8. Use of claim 7 in the preparation of a medicament for the treatment of one or more of: posi tives symptoms, negative symptoms and depressive symptoms of schizophrenia.
9. Use of a commpound or salt of claim 1 or 2 in the preparation of a medicament for the treatment of a disease selected from the group» consisting of Schizophreniza, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, and mania in bipolar disorder.
Use accordin g to any of claims 6-9, wherein said compound «or salt thereof is in the form o=f a pharmaceutical composition as defined in clairm 4.
11. The compournd or salt of claim 1 or 2 or the pharmaceutical composition of claim 3 or 4 for use in the treatment of a disease selected from the group consisting of a disease involving psychotic symptoms, schizoephrenia, anxiety disorders, azffective disorders including depression, sleesp disturbances, migraine, newmuroleptic-induced parkinsonism, abuse disorders , cocaine abuse, nicotine abus €, and alcohol abuse.
12. The compourd, salt or pharmaceutical composition accordingz to claim 11 for the treatment of schizophrenia or other psychotic disorders.
13. The compournad, salt or pharmaceutical composition according to claim 12 for the treatment: of one or more of: positives symptoms, negativ-e symptoms and depressive sy-mptoms of schizophrenia.
14. The compoumnd or salt of claim 1 or 2 or the pharmaceutical composition of claim 3 or 4 for use in the treatment of a disease selected from the group consisting o f Schizophrenia, Schizophreniform Disorder, Schizoaffective Amended sheet 2/04/2007
Disorder, Del usional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, and mania in bipolar disorder.
15. The compounad, salt or pharmaceutical composition according ®o any of claims 11-14, wherei n the patient treated with Compound I or a salt thereof is also treated with other medicament(s).
16. The compoumd, salt or pharmaceutical composition according to claim 12, wherein the p atient treated with Compound I or a salt thereo f is also treated with at least o me other medicament.
17. The compound, salt or pharmaceutical composition according to any of claims 11-16, wherein said compound or salt thereof is in the form of a pharmaceutical composition as defined in claim 4.
18. A compound _zrans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimcthylpipcrazinc or a salt thereof &or use in medicine.
19. A pharmaceuttical composition comprising the compound or salt of claim 18 together with at least one pharmaceutically acceptable carrier, filler or diluent.
20. Use of a compound or salt of claim 18 in the preparation of a medicament for the treatment of a disease selected from the group consisti ng of a disease involving psychotic symptoms, schizophrenia, Schizophren iform Disorder, Schizoaffectiwe Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, amxiety disorders, affective dis orders including depression, sleep disturbamces, migraine, neuroleptic-iduced parkinsonism, abuse disorders, cocaine abuse, nicotine abuse, or alcohol abuse.
21. Use accordin_g to claim 20 for the treatment of one or m ore of positives symptoms, nesgative symptoms and depressive symptoms of schizophrenia. Amended sheet 2/04/2007
22. The compound or salt according to claim 18 for use in thes treatment of a disease selectezd from the group consisting of a disease inveolving psychotic symptoms, sechizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, SShared Psychotic Disorder, maraia in bipolar disorder, anxiety disorders, affFective disorders including depression, sleep disturbances, migraine, neuaroleptic-induced parkinsonism, and abuse disorders.
23. The compound or salt according to claim 22, wherein the abmuse disorders are cocaine abuse, nicotine abuse, or alcohol abuse.
24. The compound or salt according to claim 22 or 23, for the tresatment of one or more positives symptoms, negative symptoms, and depressive symptoms of schizophrenia.
25. A method for manufacturing a compound of formula I (Compound I) or a salt thereof, which method comprises conversion of a compoun d of formula Va (Compound Va) in cis-configuration to the compound of forrmula I, wherein I and Va are as follows: H / ge N OH } MH (Va)
26. The method of claim 25, comprising conversion of the alcohol group of the cis-alcohol of formula Va to a suitable leaving group LG_ resulting in the compound of formula VI. Amended sheet 2/04/2007
LG os (VD
27. The method of claim 2 6, wherein LG is a halogen or a sulphonate.
28. The method of claim 2 7, wherein LG is Cl or mesylate.
29. The method of any o f claims 26-28, wherein Compound VI is precipeitated from a suitable solvent.
30. The method of claim 2-9, wherein LG is a halogen and the solvent is an al kane.
31. The method of any off claims 26-30, wherein Compound VI is rcacted with 2,2-dimethylpiperazine to obtain Compound I.
32. The method of claim 3 1, wherein Compound I is precipitated as a suitable salt.
33, The method of claim 32, wherein the formed salt is a fumarate salt or a maleate salt of Compound I.
34. The method of any of claims 26-30, comprising - reacting Compound VI with Il-protected 2,2-dimethylpiperazine (VII), wherein PG 1s a protection group, thereby obtaining a cornpound of formula VIII; and - deprotecting Compound VIII to obtain Compound I, wherein Compound VI Iand VIII are as follows: Amended sheet 2/03/2007
PG / T , PG Cl { CY ; * H (Vi) (Vil)
35. The method of claim 34, wwherein PG is selected from the group of phenylmethoxycarbonyl, tert-b utyloxycarbonyl, ethoxycarbonyl, and ben zyl.
36. A method for the preparation of Compound I or a salt thereof comprising reacting a compound of formula Via H / N Ie i N Cl oy Cr iy) (Via) with 2,2-dimethylpiperazine.
37. A method for the preparation. of Compound I or a salt thereof comp rising reacting a compound of formul a VIa Amended sheet 2/03/2007
V&/0 2005/016901 PCT/DK2004/000546 H / N " N Cl “3 CD) DH (Via) with 2,2-dimethylpiperazine in presen<e of a base.
38. The method of any of claims 25-37, wherein Compound Va is obtained by enzymatical resolution of Compound WV. OH OH V) (Va) Amended sheet 2/04/2007
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200301180 | 2003-08-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200601173B true ZA200601173B (en) | 2007-04-25 |
Family
ID=36701685
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200601173A ZA200601173B (en) | 2003-08-18 | 2004-08-18 | Trans-1(6-Chloro-3-Phenylindan-1-YL)-3,3 Dimenthylpiperazine |
| ZA200601421A ZA200601421B (en) | 2003-08-18 | 2004-08-18 | Succinate and malonate salt of trans-4-(IR,3S)-6-Chloro-3-Phenylindan-1-yl)-1, 2, 2-trimethylpiperazine and the use as a medicament |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200601421A ZA200601421B (en) | 2003-08-18 | 2004-08-18 | Succinate and malonate salt of trans-4-(IR,3S)-6-Chloro-3-Phenylindan-1-yl)-1, 2, 2-trimethylpiperazine and the use as a medicament |
Country Status (4)
| Country | Link |
|---|---|
| CN (2) | CN1839124B (en) |
| ME (1) | ME00154B (en) |
| UA (2) | UA89617C2 (en) |
| ZA (2) | ZA200601173B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010115952A1 (en) * | 2009-04-09 | 2010-10-14 | N.V. Organon | Indane derivatives |
| EP2639216B1 (en) * | 2010-11-09 | 2018-07-11 | Kaneka Corporation | Halogenated indenones and method for producing optically active indanones or optically active indanols by using same |
| JP2014501771A (en) * | 2011-01-07 | 2014-01-23 | ハー・ルンドベック・アクチエゼルスカベット | 4-((1R, 3S) -6-chloro-3-phenyl-indan-1-yl) -1,2,2-trimethyl-piperazine and 1-((1R, 3S) -6-chloro-3-phenyl -Method for resolution of indan, 1-yl) -3,3-dimethyl-piperazine |
| CN112359078A (en) * | 2021-01-12 | 2021-02-12 | 凯莱英生命科学技术(天津)有限公司 | Chiral resolution method of isobutyrate compound |
-
2004
- 2004-08-18 UA UAA200602709A patent/UA89617C2/en unknown
- 2004-08-18 CN CN2004800237257A patent/CN1839124B/en not_active Expired - Fee Related
- 2004-08-18 ZA ZA200601173A patent/ZA200601173B/en unknown
- 2004-08-18 UA UAA200909651A patent/UA108342C2/en unknown
- 2004-08-18 CN CNA2004800236381A patent/CN1835938A/en active Pending
- 2004-08-18 ZA ZA200601421A patent/ZA200601421B/en unknown
- 2004-08-18 ME MEP-2008-26A patent/ME00154B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ME00154B (en) | 2010-10-10 |
| ZA200601421B (en) | 2007-05-30 |
| MEP2608A (en) | 2010-06-10 |
| CN1835938A (en) | 2006-09-20 |
| CN1839124A (en) | 2006-09-27 |
| CN1839124B (en) | 2010-06-16 |
| UA108342C2 (en) | 2015-04-27 |
| UA89617C2 (en) | 2010-02-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5144930B2 (en) | Trans-1- (6-Chloro-3-phenylindan-1-yl) -3,3-dimethylpiperazine | |
| EP1773772B1 (en) | New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission | |
| JP2023181540A (en) | VMAT2 inhibitors for treating neurological diseases or disorders | |
| JP4857346B2 (en) | 3,5-Disubstituted phenyl-piperidines as modulators of dopamine neurotransmission | |
| CN101076517B (en) | Substituted piperidines as modulators of dopamine neurotransmission | |
| HUE028391T2 (en) | Carbonylated (aza)cyclohexanes as dopamine d3 receptor ligands | |
| MXPA06013944A (en) | New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission. | |
| CN1301972C (en) | Piperidine compounds as muscarinic antagonists | |
| JP2010529081A (en) | Novel disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission | |
| CN1302207A (en) | Combined therapy for bipolar disorders | |
| WO2018195121A1 (en) | Vmat2 inhibitor compounds and compositions thereof | |
| CN104854103A (en) | Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine d3 receptor | |
| JP2009518337A (en) | Disubstituted phenylpiperidines as modulators of cortical catecholaminergic neurotransmission | |
| TW201002328A (en) | Pyrimidinyl-piperazines useful as D3/D2 receptor ligands | |
| EA017631B1 (en) | Crystalline base of trans-1-((1r,3s)-3-phenyl-6-chloroindan-1-yl)-3,3-dimethylpiperazine | |
| ZA200601173B (en) | Trans-1(6-Chloro-3-Phenylindan-1-YL)-3,3 Dimenthylpiperazine | |
| US20040266864A1 (en) | Methods for treating depression and other CNS disorders using enantiomerically enriched desmethyl-and didesmethyl-metabolites of citalopram | |
| MX2011005036A (en) | 3-phenyl-3-methoxypyrrolidine derivatives as modulators of cortical catecholaminergic neurotransmission. | |
| EP2024363B1 (en) | N-oxides of pyridylmethylpiperazine and -piperidine derivatives | |
| AU2002250983B2 (en) | 8-{4-[3-(5-fluoro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-2-methyl-4H-benzo[1,4]oxazin-3-one mesylate with high affinity for the dopamine D2 receptor and the serotonin reuptake site | |
| JP6679621B2 (en) | Novel azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission | |
| WO2024059631A1 (en) | R-trihexyphenidyl for treatment of movement disorders | |
| EP1434764B1 (en) | Process for obtainment of enantiomers-of n-(2,6-dimethylphenyl)-1-propyl-2-piperidinocarboxamide; process for obtainment of non-racemic mixtures between the enantiomers of n-(2,6-dimethylphenyl)-1-propyl-2-piperidinocarboxamide; non racemic mixtures of enantiomers of n-(2,6-dimethylphenyl)-1-propyl-2-piperidinocarboxamide;pharmaceuticals compositions comprising said non-racemic mixtures of enantiomers of n-(2,6-dimethylphenyl)-1-propyl-2-piperidinocarboxamide |