Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to form two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR and DDCAR are pharmacologically active metabolites with _in vitro_ receptor binding profiles similar to the parent drug. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR can be metabolized by CYP3A4 to form a hydroxylated metabolite.
Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite.
... Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug.
... This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (< or = 4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed. Steady state was reached within 1-2 weeks for cariprazine and desmethyl-cariprazine, 4 weeks for didesmethyl-cariprazine, and 3 weeks for total active moieties. Cariprazine and desmethyl-cariprazine levels decreased >90% within 1 week after the last dose, didesmethyl-cariprazine decreased approximately 50% at 1 week, and total active moieties decreased approximately 90% within 4 weeks. Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was approximately 1 week. ...
IDENTIFICATION AND USE: Cariprazine, as the drug Vraylar, is indicated for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. HUMAN EXPOSURE AND TOXICITY: A patient who accidentally overdosed experienced orthostasis and sedation, and recovered later the same day. Elderly patients with dementia-related psychosis treated with Vraylar are at an increased risk of death. Vraylar is not approved for the treatment of patients with dementia-related psychosis. Cariprazine was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay; its metabolite DDCAR was clastogenic and induced structural chromosomal aberration in the in vitro human lymphocyte chromosomal aberration assay. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. ANIMAL STUDIES: Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures (AUC) of total cariprazine. Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following oral daily administration for 13 weeks and/or 1 year and retinal degeneration/atrophy in the rat following oral daily administration for 2 years. Oral administration of cariprazine to pregnant rats during pregnancy and lactation caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the Maximum Recommended Human Dose (MRHD) of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays. Cariprazine was not mutagenic in the in vitro bacterial reverse mutation assay, nor clastogenic in the in vivo mouse bone marrow micronucleus assay. However, cariprazine increased the mutation frequency in the in vitro mouse lymphoma assay under conditions of metabolic activation. There was no increase in the incidence of tumors following daily oral administration of cariprazine to rats for 2 years and to mice for 6 months at doses which are up to 4 and 19 times respectively, the MRHD.
Serum aminotransferase elevations above 3 times the upper limit of normal occurred in 2% to 4% of patients treated with cariprazine in preregistration studies compared with 0.7% to 2% of placebo recipients. Elevations above 5 times ULN were rare
◉ Summary of Use during Lactation:No information is available on the use of cariprazine during breastfeeding. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date. Cariprazine has little to no effect on serum prolactin levels.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
The most clinically relevant drug concentration equates to the combined systemic concentration of cariprazine plus desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), the two main pharmacologically active metabolites of cariprazine. After single dose administration of cariprazine, the peak plasma cariprazine concentration occurred in approximately three to six hours. In healthy volunteers, the Tmax following oral administration was 3.6 hours for cariprazine, 6.5 hours for DCAR, and 18.1 hours for DDCAR. The steady-state was reached dose-proportionally within three weeks for cariprazine, DCAR, and DDCAR in patients with schizophrenia. Administration of a single dose of 1.5 mg cariprazine capsule with a high-fat meal did not significantly affect the Cmax and AUC of cariprazine or its metabolite, desmethyl cariprazine (DCAR).
Following administration of 12.5 mg/day cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose being excreted in urine as unchanged parent drug.
... This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (< or = 4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed. Steady state was reached within 1-2 weeks for cariprazine and desmethyl-cariprazine, 4 weeks for didesmethyl-cariprazine, and 3 weeks for total active moieties. Cariprazine and desmethyl-cariprazine levels decreased >90% within 1 week after the last dose, didesmethyl-cariprazine decreased approximately 50% at 1 week, and total active moieties decreased approximately 90% within 4 weeks. Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was approximately 1 week. Incidence of treatment-emergent adverse events was 97.4%; 15.8% of patients discontinued due to adverse events. No abnormal laboratory values or major differences from baseline in extrapyramidal symptoms were observed. Cariprazine and its active metabolites reached steady state within 4 weeks, and exposure was dose proportional over the range of 3-9 mg/day. Once-daily cariprazine was generally well tolerated in adult patients with schizophrenia.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
卡利拉嗪及其主要活性代谢物高度结合（91%至97%）到血浆蛋白。
Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins.
Following administration of 12.5 mg/day cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose was excreted in urine as unchanged cariprazine.
PROCESS FOR THE PREPARATION OF PIPERAZINE COMPOUNDS AND HYDROCHLORIDE SALTS THEREOF
申请人：Czibula Laszlo
公开号：US20110275804A1
公开（公告）日：2011-11-10
The invention relates to a new process for the preparation of compounds of general formula (I) wherein
R
1
and R
2
represent independently hydrogen or
C
1-6
alkyl with straight or branched chain optionally substituted with aryl group, or
C
2-7
alkenyl containing 1-3 double bonds, or
monocyclic, bicyclic or tricyclic aryl optionally substituted with one or more C1-6 alkoxy, trifluoro-C
1-6
alkoxy, C
1-6
-alkoxycarbonil, C
1-6
alkanoyl, aryl, C
1-6
alkylthio, halogen or cyano, or
optionally substituted monocyclic, bicyclic or tricyclic C
3-14
cycloalkyl group,
R
1
and R
2
together with the adjacent nitrogen form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen, or sulphur atoms
and hydrochloric acid alts and/or hydrates and/or solvates thereof, by dissolving or suspending trans 4-2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexylamine of formula (III) or a salt or a hydrate or a solvate thereof in an inert solvent in the presence a base then adding a carbonic acid derivative of general formula (VI) wherein R is alkyl with C
1-6
straight or branched chain or C
1-2
fully halogenated alkyl, Z is —O—R or —X, wherein R is as described above, X is halogen, and reacting the compound of general formula (IV) obtained wherein R is as described above, in situ or, optionally in isolated state with an amine of general formula (V) wherein R
1
and R
2
are as described above to obtain the compound of general formula (I) and then optionally forming the hydrochloride salts and/or hydrates and/or solvates thereof.
[EN] NOVEL PROCESSES FOR THE PREPARATION OF TRANS-N-{4-[2-[4-(2,3-DICHLOROPHENYL)PIPERAZINE-1-YL]ETHYL] CYCLOHEXYL}-N',N'-DIMETHYLUREA HYDROCHLORIDE AND POLYMORPHS THEREOF<br/>[FR] NOUVEAUX PROCÉDÉS POUR LA PRÉPARATION DE CHLORHYDRATE DE TRANS-N-{4-[2-[4-(2,3-DICHLOROPHÉNYL)PIPÉRAZINE-1-YL]ÉTHYL] CYCLOHEXYL}-N',N'-DIMÉTHYL URÉE ET POLYMORPHES DE CELUI-CI
申请人：MSN LABORATORIES PRIVATE LTD R&D CENTER
公开号：WO2019016828A1
公开（公告）日：2019-01-24
The present invention relates to novel processes for the preparation of trans- N-4-[2- [4-(2,3-dichloro phenyl) piperazine-1-yl] ethyl] cyclohexyl} -N',N'-dimethylurea hydrochloride represented by the following structural formula-1a and polymorphs thereof. (I) The present invention also relates to novel intermediate compounds which are useful for the preparation of compound of formula-1a.
