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Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with awavelength of 693 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels.[1][2]
Verteporfin is also used off-label for the treatment of central serous retinopathy.[3]
Verteporfin, otherwise known as benzoporphyrin derivative (trade name Visudyne®), is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with a wavelength of 693 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels.
Verteporfin is given intravenously, 15 minutes before laser treatment.[1]
VISUDYNE® (verteporfin) for Injection is a light activated drug used inphotodynamic therapy. The finished drug product is a lyophilized dark green cake. Verteporfin is a 1:1 mixture of two regioisomers (I and II), represented by the following structures:
The chemical names for the verteporfin regioisomers are:
9-methyl (I) and 13-methyl (II) trans-(±)-18-ethenyl-4,4a-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H, 25H-benzo[b]porphine-9,13-dipropanoate
The molecular formula is C41H42N4O8 with a molecular weight of approximately 718.8. Each mL of reconstituted VISUDYNE contains:
| ACTIVE: | Verteporfin, 2 mg |
| INACTIVES: | Lactose, egg phosphatidylglycerol, dimyristoyl phosphatidylcholine, ascorbyl palmitate and butylated hydroxytoluene |
Most common side effects are blurred vision, headache, and local effects at the injection site. Also, photosensitivity; it is advised to avoid exposure to sunlight and unscreened lighting until 48 hours after the injection of verteporfin.[1]
None known. Verteporfin has no influence on the liver enzyme CYP3A4, which metabolises many pharmaceutical drugs.[1]
…………………..
http://www.google.com/patents/WO2011017809A1?cl=en
Verteporfin (CAS # 129497-78-5) is a benzoporphyrin derivative which has been used clinically for photodynamic therapy of age related macular degeneration (23).
Verteporfin is photoactivated for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular
degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with a wavelength of 693 ran in the presence of oxygen, the photoactivated verteporfin produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels. Benzoporphoryrins, are described for example, in US patents 5,095,030, 5,214,036, and 6,008,241.
Verteporfin (CAS # 129497-78-5) as used herein may include the two regioisomers as shown below:
and the 2 entantiomers of each of the two regioisomers as shown below:
The verteporfin as disclosed herein contains at least one chiral center and thus may exist in various stereoisomeric forms. If desired, such stereoisomers, including enantiomers, may be separated using techniques standard in the art (for example, chiral columns). However, racemic mixtures or mixtures containing more than one diastereomer may also be used and are contenplated herein. However, the compounds tested herein were in either of the trans entantiomers shown above. The compounds shown in Formulas IA, IB, Tables 1, 2 and Figure 10, are representative of the individual optical isomers, enantiomers or diastereomers as the case may be, as well as mixtures of these individual chiral isomers.
Visudyne™, as used herein, is the liposomal formulation of verteporfin used in humans for photodynamic therapy. Visudyne™ is given intravenously, usually within 15 minutes prior to laser treatment to eliminate the abnormal blood vessels in the eye in the treatment of wet macular degeneration. The verteporfin compound accumulates in these abnormal blood vessels and, when stimulated by a nonthermal red light laser with a wavelength of 693 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels. Patients given Visudyne™ experience photosensitivity and are advised to avoid exposure to sunlight and unscreened lighting for at least 48 hours after the injection of verteporfin.
In contrast to the current use of verteporfin in photodynamic therapy, subjects administered the BPDs described herein, in accordance with the methods and uses described herein, do not require photoactivation of the BPD via nonthermal red light laser with a wavelength of 693 nm or otherwise. The activity of the BPDs to inhibit early stage autophagy is independent of the activity associated with photoactivation and would likely be hindered by photoactivation. Accordingly, a person of skill in the art would appreciate that the precautions associated with photosensitivity should also apply to the present methods and uses (i.e. avoid exposure to sunlight and unscreened lighting for at least 48 hours after the injection of of the BPD).
| Patent | Submitted | Granted |
|---|---|---|
| Photodynamic therapy for the treatment of hair loss [US7090691] | 2004-01-22 | 2006-08-15 |
| PHOTOTHERAPY METHODS AND DEVICES COMPRISING EMISSIVE ARYL-HETEROARYL COMPOUNDS [US2012015998] | 2012-01-19 | |
| PHOTOTHERAPY DEVICES AND METHODS COMPRISING SUBSTITUTED CARBAZOLE COMPOUNDS [US2012016449] | 2012-01-19 | |
| PHOTODYNAMIC THERAPY FOR THE TREATMENT OF HAIR LOSS [US2008056996] | 2008-03-06 | |
| FACTOR VII CONJUGATES FOR SELECTIVELY TREATING NEOVASCULARIZATION DISORDERS [US2008206227] | 2008-08-28 | |
| Factor VII conjugates for selectively treating neovascularization disorders [US2006052286] | 2006-03-09 | |
| Methods of treating neuralgic pain [US2004220167] | 2004-11-04 |
| Systematic (IUPAC) name | |
|---|---|
| 3-[(23S,24R)-14-ethenyl-5-(3-methoxy-3-oxopropyl)-22,23-bis(methoxycarbonyl)-4,10,15,24-tetramethyl-25,26,27,28-tetraazahexacyclo[16.6.1.13,6.18,11.113,16.019,24]octacosa-1,3,5,7,9,11(27),12,14,16,18(25),19,21-dodecaen-9-yl]propanoic acid | |
| Clinical data | |
| Trade names | Visudyne |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a607060 |
| Pregnancy cat. |
|
| Legal status | |
| Routes | Intravenous |
| Identifiers | |
| CAS number | 129497-78-5  |
| ATC code | S01LA01 |
| PubChem | CID 5362420 |
| DrugBank | DB00460 |
| ChemSpider | 21106402 |
| UNII | 0X9PA28K43 |
| KEGG | D01162 |
| ChEBI | CHEBI:60775 |
| ChEMBL | CHEMBL2218885  |
| Chemical data | |
| Formula | C41H42N4O8 |
| Molecular mass | 718.794 g/mol |
CARIPRAZINE
CAS 839712-12-8 (free base)
CAS 1083076-69-0…HYDROCLORIDE SALT
trans-N-[4-[2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N’,N’-dimethylurea
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea
trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine
trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea
IN PHASE 3 FOR MAJOR DEPRESSION
Cariprazine (RGH-188) is an antipsychotic drug under development by Gedeon Richter. It acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor.[1] Positive Phase III study results were published for schizophrenia and maniaearly 2012, while Phase II studies in bipolar disorder I, and for bipolar depression are in progress.[2] Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder [3]
Forest Laboratories obtained a license on development (from the Richter – Hungary) and exclusive commercial rights in the US in 2004.
NEWS………….DUBLIN and BUDAPEST, Hungary, Jan. 6, 2015 /PRNewswire/ — Actavis plcand Gedeon Richter Plc. today announced that the U.S. Food and Drug Administration (FDA) has acknowledged receipt of Actavis’ New Drug Application (NDA) resubmission for its atypical antipsychotic cariprazine, a potent dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors. The Prescription Drug User Fee Act (PDUFA) date is expected to be in the second quarter of 2015…….
Production building of the company in Budapest
Cariprazine is currently in clinical trials for schizophrenia and bipolar disorder. It has also been investigated as a potential adjunct in treatment-resistant major depressive disorder.[4]
Illustrated Pill Packaging
The most prevalent side effects for cariprazine include akathisia, insomnia, and weight gain. Cariprazine does not appear to impact metabolic variables or prolactin levles, and unlike many other antipsychotics, does not increase the electrocardiogram (ECG) QT interval. In short term clinical trials extrapyramidal effects, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation were observed. One review characterized the frequency of these events as “not greatly different from that seen in patient treated with placebo”[5] but a second called the incidence of movement-related disorders “rather high”[6][7] .
Cariprazine acts as an antipsychotic that is effective against the positive and negative symptoms of schizophrenia.[8] Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist. It also has a higher affinity for D3 receptors. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia.[9] Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine’s high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors.[8] Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).[8][10] In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted.[8] This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.
Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity.[11] In monkey studies, the administration of increasing does of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94 % occupied, while at the lowest dose (1 μg/kg), receptors were 5 % occupied.[10]
| Receptor | Ki (nM)[4] | Pharmacodynamic action[4] |
|---|---|---|
| 5-HT1A | 3 | Partial agonism |
| 5-HT2A | 19 | Inverse agonism/antagonism |
| 5-HT2B | 0.58 | Inverse agonism/Antagonism |
| 5-HT2C | 134 | Inverse agonism/Antagonism |
| 5-HT7 | 111 | Antagonism |
| D2S | 0.69 | Partial agonism |
| D2L | 0.49 | Partial agonism |
| D3 | 0.085 | Partial agonism |
| H1 | 23 | Inverse agonism/antagonism |
Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic.[2] In rats, the oral bioavailability was 52 % (with a dose of 1 mg/kg).[7]
………………………
PATENT
http://www.google.com/patents/EP1663996A1?cl=en
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 )
Example 1 1-(2,3-dichlorophenyl)-[1,4]diazepine (starting material)
2.25 g (10 mmol) 1-bromo-2,3-dichloro-benzene was dissolved in dry toluene (50 ml), 2.3 (11 mmol) of [1 ,4]diazepine-1 -carboxylic acid tert-butylester was added followed by 0.2 g BINAP (2,2-bis(diphenylρhosphino)-1 ,1′-binaphtyl), 85 mg tris(dibenzylideneacetone)dipalladium(0) and 1.2 g (12mmol) sodium-tert-butoxyde. The reaction mixture was refluxed for eight hours and filtered. The organic layer was washed with water, dried and evaporated in vacuo. The residue was purified by chromatography and deprotected at 10 °C using 20 ml ethylacetate saturated with gaseous hydrochloric acid, the precipitate was filtered giving 2.1 g (yield: 75 %) hydrochloride salt of the title compound, melting at 182-3 °C. Example 2 Trans-N-{4-[2-[4-(2,3-dichloro-phenyl)-hexahydro-[1 ,4]diazepin-1-yl]-ethyl]- cyclohexyl}-carbamic acid tert-butylester (intermediate) 0.7 g (2.5 mmol) of 1 -(2,3-dichlorophenyl)-[1 ,4]diazepine hydrochloride and
0.6 g (2.5 mmol) of frat?s-2-{1 -[4-(N-tert-butyloxycarbonyl)amino]cyclohexyl}- acetaldehyde were dissolved in dichloroethane (35 ml), 0.35 ml (2.5 mmol) triethylamine was added, then 0.79 g (3.7 mmol) sodium triacetoxyborohydride was added portionswise and the reaction mixture was stirred for 20 hours at ambient temperature, then 20 % potassium carbonate solution in water (20 ml) was added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to give the title compound 1 .0 g (yield: 85.8 %), m.p.: 95-8 °C. Example 3
Trans-4-[2-[4-(2,3-dichloro-phenyl)-hexahydro-[1 ,4]diazepin-1-yl]-ethyl]- cyclohexylamine (intermediate)
0.93 g (2.1 mmol) frarjs-N-{4-[2-[4-(2,3-dichloro-phenyl)-hexahydro- [1 ,4]diazepin-1 -yl]-ethyl]-cyclohexyl}-carbamic acid tert-butylester was deprotected at
10 °C using 15 ml ethylacetate saturated with gaseous hydrochloric acid, after 4 hours the precipitate was filtered giving 0.91 g (yield: 98 %) dihydrochloride salt of the title compound, melting at 260-6 °C. Method A
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yi]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 ) 1 .39g (3 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-ρiperazin-1 -yl]-ethyl}- cyclohexyl-amine trihydrochloride was suspended in dichloromethane (100 ml), triethylamine (2.1 ml, 15 mmol) was added followed by 0.30 ml (3.3 mmol) N,N- dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature, filtered. The filtrate was washed with water (2 x 20 ml), dried and evaporated in vacuo. Recrystallizing from methanol gave the title compound (0.83 g, 65 %), melting at 212-4 °C.
Method B
7rans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-ethyl- urea (compound 2) 0.56g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}- cyclohexyl-amine was dissolved in dry dichloromethane (20 ml), ethylisocyanate (0.1 ml, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was stirred with water, the precipitate was filtered, giving the title compound (0.33 g, 65 %). Melting point:
235-8 °C.
Method C rrans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 )
0.56g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}- cyclohexyl-amine trihydrochloride was suspended in dry dichloromethane (50 ml), triethylamine 0.77 ml, 6 mmol) was added and 0.13g (0.44 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature dimetilamine hydrochloride (0.49 g, 6 mmol) followed by triethylamine (0.84 ml, 6 mmol) was added and the stirring was continued for 20 hours. The mixture was filtered, the filtrate washed with water, dried and evaporated in vacuo. Recrystallizing the product from methanol gave the title compound (0.27 g, 52 %). Melting point: 212-4 °C.
……………………
PATENT
http://www.google.com/patents/US20090023750
U.S. Patent Publication No. 2006/0229297 discloses (thio)-carbamoyl-cyclohexane derivatives that are D3 and D2 dopamine receptor subtype preferring ligands, having the formula (I):
(I)
wherein R1, R2, X, and n are as defined therein. One particular compound disclosed therein is trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, which is also known as trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, the structural formula for which is shown below:
Compounds of formula (I) act as a dopamine receptor antagonists, particularly D3/D2 receptor antagonists, and are useful in the treatment and prevention of pathological conditions which require modulation of dopamine receptors.
In some cases, an appropriate salt of an active may improve certain properties suitable for pharmaceutical compounds (i.e., stability, handling properties, ease of large scale synthesis, etc.). However, selection of a suitable salt for a particular active agent is not always straightforward, since the properties of salts of different compounds formed with the same salt forming agent may differ greatly. Moreover, formation of particular salts of a compound possessing more than one basic centre may be difficult to achieve in high yield due to formation of multiple products.
…………………..
see
WO 2011073705
http://www.google.com/patents/WO2011073705A1?cl=en
We have surprisingly found that by reacting trans 4-{2-[4-(2,3-dichlorophenyl)- piperazine-l-yl]-ethyl}-cyclohexylamine of formula (III)
with a carbonic acid derivative of general formula (VI)R-O-CO-Z (VI)
then reacting the compound of general formula (IV) obtained
with an amine derivative of general formula (V)
get the compounds of general formula (I)
EXAMPLES
The invention is illustrated by the following non-limiting examples.
Example 1
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid methylester 6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The so obtained suspension was added to a solution of 2.3 ml (0.03 mol) methyl chloroformate in 25 ml of dichloromethane at a temperature between 5-10°C. The reaction mixture obtained was stirred at a temperature between 20-25°C for 3 hours then extracted with 3×150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue was recrystallized from methanol. In this manner 4.5 g of the title product was obtained.
Yield: 72 %.
Melting point: 143-147 °C
Example 2
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid isopropylester
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C-on for one hour. The suspension was added to a solution of 3.7 g (0.03 mol) of isopropyl chloroformate in 30 ml of toluene at a temperature between 5-10°C. The reaction mixture was stirred at a temperature between 20-25°C for 3 hours and then extracted with 3×150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue obtained was recrystallized from isopropanole.
In this manner 4,4 g of title compound was obtained. Yield: 67 %.
Melting point: 128-131°C
Example 3
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 130 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.6 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C Example 4
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyI}-N,N-dimethylcarbamoyl- cyclohexylamine 4.4 g (0.011 mol) of trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}- cyclohexyl)-carbamic acid methylester was dissolved in 120 ml of dichloromethane. The solution obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (100 ml, 0.3 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 100 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 120 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 4.3 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C
Example 5
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine hydrochloride 6.45 g (0.015 mol) dihydrochloride of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes 100 ml of distilled water was added to the reaction mixture under stirring. Then the pH of the aqueous phase is adjusted to 2-3 by adding concentrated hydrochloric acid and the reaction mixture was concentrated to 130 ml, additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %
Melting point: 221-224 °C
Example 6
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoil- cyclohexylamine hydrochloride 6.72 g (0.015 mol) dihydrochloride monohydrate of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25 °C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0,12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added and the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum then additional 70 ml of water was added and the mixture was concentrated to 170 ml. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %.
Melting point: 221-224 °C
………………………………………
SEE
http://www.google.com/patents/WO2014031162A1?cl=en
……………………………….
PAPER
Cariprazine, a potential atypical antipsychotic agent has been identified during the optimization of novel series of 4-aryl-piperazine derivatives. The recently available top line results from pivotal clinical trials demonstrated the safety and efficacy of cariprazine in bipolar mania and schizophrenia indications.
………………………………………….
Journal of Medicinal Chemistry, 2013 , vol. 56, 22 pg. 9199 – 9221
http://pubs.acs.org/doi/abs/10.1021/jm401318w
Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (2).(ref…………Ágai-Csongor, É.; Domány, G.; Nógrádi, K.; Galambos, J.; Vágó, I.; Keserű, G. M.; Greiner, I.; Laszlovszky, I.; Gere, A.; Schmidt, É.; Kiss, B.; Vastag, M.; Tihanyi, K.; Sághy,K.; Laszy, J.; Gyertyán, I.; Zájer-Balázs, M.; Gémesi, L.; Kapás, M.; Szombathelyi,Z.Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2receptors Bioorg. Med. Chem. Lett. 2012, 22, 3437– 3440)
the metabolite of the present invention is selected from:
0.8 g (1.6 mmol) trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea was dissolved in dichloromethane (60 ml). A solution of 0.54 g (2.4 mmol) 3-chloro-perbenzoic acid in dichloromethane (10 ml) was dropped in and the reaction mixture stirred for 24 hours at room temperature. The reaction was monitored by TLC. The solution was washed twice with saturated NaHCO3 solution, the organic layer dried and evaporated in vacuo. Flash chromatography gave 0.45 g (63.3%) of the title compound melting at 175-8° C.
Example 2Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea (compound C)
0.92 g (2 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (60 ml), triethylamine (1.26 ml, 9 mmol) was added followed by 0.21 ml (2.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature. The solution was washed with water (2×10 ml), dried and evaporated in vacuo. Purification with flash chromatography gave 0.66 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, melting at 196-8° C. This product was dissolved in dichloromethane (60 ml), then 6.4 ml (6.4 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added, followed by 25 ml saturated NaHCO3 solution. After separation the organic layer was dried and evaporated in vacuo. Purification with flash chromatography gave 0.4 g of the title compound, melting at 278-80° C.
Example 3Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea (compound B)
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine (1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature methylamine (33% solution in ethanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea (0.86 g, 65%) melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.34 g of title compound, melting at 237-41° C.
Example 4Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea (compound A)
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine 1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature ammonia (20% solution in methanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave 0.86 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.37 g of title compound, melting at 195-8° C.
| WO2005012266A1 * | May 21, 2004 | Feb 10, 2005 | Richter Gedeon Vegyeszet | (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists |
| WO2008142461A1 * | May 15, 2008 | Nov 27, 2008 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| WO2010070370A1 * | Dec 18, 2009 | Jun 24, 2010 | Richter Gedeon Nyrt. | Process for the preparation of piperazine compounds and hydrochloride salts thereof |
| WO2010070371A1 * | Dec 18, 2009 | Jun 24, 2010 | Richter Gedeon Nyrt. | Process for the preparation of piperazine derivatives |
| HU0302451A2 | Title not available |
| WO1996007331A1 * | Sep 8, 1995 | Mar 14, 1996 | Helena Halttunen | Composition comprising co-crystals, method for its manufacture, and its use |
| US20090023750 * | May 9, 2008 | Jan 22, 2009 | Richter Gedeon Nyrt. | Novel salts of piperazine compounds as d3/d2 antagonists |
| US20090030007 * | May 9, 2008 | Jan 29, 2009 | Forest Laboratories Holdings Limited | crystalline form of trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea hydrochloride (Form III) Cariprazine {RGH-188); Dysfunction of the dopaminergic neurotransmitter system is involved in the pathology of several neuropsychiatric and neurodegenerative disorders |
| US20090054455 * | Feb 2, 2007 | Feb 26, 2009 | Dr. Reddy’s Laboratories Ltd. | Aripiprazole co-crystals |
| US20100137335 * | May 15, 2008 | Jun 3, 2010 | Eva Againe Csongor | Metabolites of (thio) carbamoyl-cyclohexane derivatives |
Richter Gedeon Gyógyszergyár
I was sitting in the lobby of my accountant’s office, flipping absentmindedly through a magazine when she walked in. I’ve never had a visceral reaction as when I saw her walk through that door. There was just something about her; I felt head over heels… My heart started racing and I had butterflies in my stomach…
This is the amazing time when you are truly love-struck. With an irresistible cocktail of chemicals, our brain entices us to fall in love. But is it really us or is it yet another nature’s trick to keep our species alive?
Scientists agree that there are three stages and processes in love:
: Dopamine and AdrenalineWhen you fall in love, your brain starts sending signals before you can even blink. Your heart races and palms sweat: adrenaline is getting released from neurons. Then, when you are close to your…
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Epelsiban
557296
GSK-557296
GSK-557296-B
(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione
(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione
(3R, 6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1-[(1R)- 1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1 S)-1-methylpropyl]-2,5- piperazinedione
Glaxo Group Limited INNOVATOR
Epelsiban (GSK-557,296-B)[1][2] is an oral drug which acts as a selective, sub-nanomolar (Ki=0.13 nM) oxytocin receptor antagonist with >31000-fold selectivity over the related vasopressin receptors and is being developed by GlaxoSmithKline for the treatment of premature ejaculation in men.[3][4]
benzenesulfonic acid;(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione,CAS 1159097-48-9
UNII-H629P9T4UN, GSK557296B, Epelsiban besylate (USAN), Epelsiban besylate [USAN], 1159097-48-9, H629P9T4UN
GSK-557296 is being developed in early clinical studies at GlaxoSmithKline for enhancement of embryo and or blastocyst implantation in women undergoing IVF treatment. The product has been in phase II clinical development for the treatment of premature ejaculation.
Preterm labor is a major clinical problem leading to death and disability in newborns and accounts for 10% of all births and causes 70% of all infant mortality and morbidity.
Oxytocin (OT) is a potent stimulant of uterine contractions and is responsible for the initiation of labor via the interaction with the OT receptors in the mammalian uterus. OT antagonists have been shown to inhibit uterine contractions and delay preterm delivery. So there is increasing interest in OT antagonists because of their potential application in the prevention of preterm labor. Although several tocolytics have already been approved in clinical practice, they have harmful maternal or fetal side effects.
The first clinically tested OT antagonist atosiban has a much more tolerable side effect profile and has recently been approved for use in Europe. However, atosiban is a peptide and a mixed OT/vasopressin V1a receptor antagonist that has to be given by iv infusion and is not suitable for long-term maintenance treatment, as it is not orally bioavailable.
Hence there has been considerable interest in overcoming the shortcomings of the peptide OT antagonists by identifying orally active nonpeptide OT antagonists with a higher degree of selectivity toward the vasopressin receptors (V1a, V1b, V2) with good oral bioavailability. Although several templates have been investigated as potential selective OT antagonists, few have achieved the required selectivity for the OT receptor vs the vasopressin receptors combined with the bioavailability and physical chemical properties required for an efficacious oral drug.
Therefore our objective was to design a potent, orally active OT antagonist with high levels of selectivity over the vasopressin receptor with good oral bioavailability in humans that would delay labor safely by greater than seven days and with improved infant outcome, as shown by a reduced combined morbidity score.
| Patent | Submitted | Granted |
|---|---|---|
| Compounds [US7919492] | 2010-12-02 | 2011-04-05 |
| Piperazinediones as Oxytocin Receptor Antagonists [US7550462] | 2007-11-01 | 2009-06-23 |
| Compounds [US8202864] | 2011-06-23 | 2012-06-19 |
| Novel compounds [US2009247541] | 2009-10-01 |
………………………………………
PATENT
https://www.google.com/patents/US7919492
Example 3
Method A
(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione
as a white lyophilisate (88 mg, 23%) after freeze-drying from 1,4-dioxane
HPLC Rt=2.70 minutes (gradient 2); m/z [M+H]+=519
1H NMR (CDCl3) δ 7.49 (d, 1H), 7.27-7.15 (m, 4H), 7.10 (d, 1H), 6.68 (s, 1H), 6.40 (d, 1H), 4.10 (dd, 1H), 4.01 (d, 1H), 3.74-3.52 (m, 5H), 3.28-3.07 (m, 5H), 2.97-2.84 (m, 2H), 2.79-2.71 (m, 1H), 2.62 (s, 3H), 2.59 (s, 3H), 1.65-1.53 (m, 1H), 0.98-0.80 (m, 2H), 0.70 (t, 3H), 0.45 (d, 3H).
Example 3
Method B
(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione
A suspension of {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride (5.0 g, 10.3 mmol) (intermediate 5) in dry dichloromethane (50 ml) was treated with 1,1-carbonyldiimidazole (2.6 g, 16 mmol) and the reaction mixture was stirred under nitrogen for 18 hours. Morpholine (4.8 ml, 55 mmol) was added and the resultant solution was left to stand under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was separated between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. This was applied to a basic alumina cartridge (240 g) and eluted using a gradient of 0-7.5% methanol in diethyl ether (9CV), 7.5-10% methanol in diethyl ether (1CV) and 10% methanol in diethyl ether (1CV). The required fractions were combined and evaporated in vacuo to give (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione as a white solid (2.4 g, 45%).
HPLC Rt=2.72 minutes (gradient 2); m/z [M+H]+=519
………………………………………
WO 2011051814
http://www.google.com/patents/WO2011051814A1?cl=en
This invention relates to novel crystalline forms of (3R, 6R)-3-(2,3-dihydro-1 H- inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1 S)-1 – methylpropyl]-2,5-piperazinedione benzenesulfonate salt, processes for their preparation, pharmaceutical compositions containing them and to their use in medicine. The benzenesulfonate salt of Compound A is represented by the following structure:
In one aspect, the present invention provides a crystalline form of {3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate, wherein said crystalline form provides an X-ray powder diffraction pattern substantially in accordance with Figure 1 .
In another aspect, the invention encompasses a crystalline form of (3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate, wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising the peaks:
In an additional aspect, the invention includes a crystalline form of {3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said compound is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 2.
In certain aspects, the invention encompasses a crystalline form of (3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said compound is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 2 In one aspect, the invention also provides a crystalline form of {3R, 6R)-3-(2,3- dihydro-1 H-inden-2-yl)-1-[(1 R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]- 6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising the peaks:
Experimental
Process Scheme
Stage 4
Acetone / Water Recrystallisation
Compound A-form I Ste8e 5 Besylate salt
MW 676.83 Acetone / Water
Recrystallisation MW 676.83 Process description for isolation of Compound A-Form 1
Stage 0
methyl d-alloisoleucinate hydrochloride (Compound 2) was charged to ethyl acetate. A solution of potassium carbonate in water was then added. The mixture was then stirred vigorously at room temperature for 1 hour. The two layers were separated and the aqueous layer further extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layers were then concentrated in vacuo and filtered to yield methyl D-alloisoleucinate (Compound 3) as a pale yellow oil.
Stage 1
2,6-dimethyl-3-pyridinecarbaldehyde (Compound 4) in methanol at ambient temperature was treated with D-alloisoleucinate (Compound 3) in methanol followed by 2,2,2- trifluoroethanol and the reaction mixture was warmed to 40°C. When formation of the intermediate imine (methyl A/-[(2,6-dimethyl-3-pyridinyl)methylidene]-D-alloisoleucine) was complete Compound 5 was added followed by 1-isocyano-2- [(phenylmethyl)oxy]benzene (Compound 6) and the reaction mixture was stirred at 40°C until formation of Compound 7 was deemed complete.
Stage 2
Palladium on carbon catalyst was treated with a solution of Compound 7 in methanol and 2,2,2-trifluoroethanol and diluted with acetic acid. The vessel was purged with nitrogen and the reaction mixture warmed to 50°C and hydrogenated at 4.0-4.5 barg. When the reaction was deemed complete it was cooled to ambient temperature and the catalyst removed by filtration and washed through with methanol. The organic solution of 2- {(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1-piperazinyl}- 2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8) was concentrated at reduced pressure and then diluted with /‘so-propyl acetate and concentrated at reduced pressure.
The residue was diluted with /‘so-propyl acetate and washed with aqueous ammonia. The aqueous phase was separated and extracted into another portion of /‘so-propyl acetate. The combined organic phases were washed with water, concentrated by distillation at reduced pressure, diluted with /‘so-propyl acetate and concentrated by distillation at reduced pressure, to leave a concentrated solution of 2-{(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1 – piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8). The product was finally dissolved in 1 ,4-dioxane for the next stage and stored into drums.
Stage 3 Solution of 2-{(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1 – piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8) in 1 ,4-dioxane was treated with 1 ,1 ‘-carbonyl diimidazole at ambient temperature to form a solution containing (3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1 -[1-(2,6-dimethyl-3-pyridinyl)- 2-oxo-2-(2-oxo-1 ,3-benzoxazol-3(2H)-yl)ethyl]-6-[(1 S)-1 -methylpropyl]-2,5- piperazinedione (Compound 9).
In a separate vessel morpholine in 1 ,4-dioxane was heated to 80-85°C. The solution containing (3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1-[1 – (2,6-dimethyl-3-pyridinyl)-2-oxo-2-(2-oxo-1 ,3-benzoxazol-3(2H)-yl)ethyl]-6-[(1 S)-1- methylpropyl]-2,5-piperazinedione (Compound 9) was slowly added to the morpholine in 1 ,4-dioxane. The reaction mixture was stirred for one hour at 80-85°C and cooled before concentration by distillation at reduced pressure.
The concentrated solution of Compound A was diluted with /‘so-propyl acetate and washed with aqueous sodium hydroxide followed by water. The /so-propyl acetate solution of COMPOUND A was then concentrated by distillation at reduced pressure and cooled to ambient temperature. The concentrated solution of Compound A was then diluted with acetone and treated with benzenesulfonic acid and seed crystals were added and the reaction mixture stirred until crystallisation occurred. The slurry of Compound A besylate was heated to 50°C, a temperature cycle was performed, and finally the slurry was cooled to -10°C and isolated by filtration. The filter cake was washed with cold acetone (-10°C) to give Compound A besylate (intermediate grade) as a wet cake.
Yield: 44% from Compound 5
39% from Compound 5
Stage 4
Compound A besylate (intermediate grade wet cake, Compound A besylate ) was suspended in acetone (17.4 vol including acetone content of wet cake) and heated to 55- 60°C. Water (0.66 vol) was added until dissolution was observed. The reaction mixture was then filtered into another vessel and the lines washed through with acetone (3.2 vol). The temperature of the reaction mixture was adjusted to 45-50°C before the addition of seed crystals (0.00025wt). When crystallisation was complete the reaction mixture was cooled to 20-25°C and stirred at 20-25°C for 30mins.
The reaction mixture was heated to 45-50°C and stirred at 45-50°C for 30mins. The reaction mixture was cooled to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was heated to 45-50°C and stirred at 45-50°C for 30mins. The reaction mixture was cooled to -3-2°C over 4.5 h and stirred for at least 1 h before the product was isolated by filtration. The wet cake was washed with acetone at 0°C (3 x 3.1 vol) and blown dry before being unloaded. COMPOUND A besylate was dried at 50°C under vacuum for 3 days. Compound A besylate was then milled. Yield: 66% Stage 5
Compound A besylate (OBU-D-02) was suspended in acetone (8 vol) and water (1 .1 vol) and heated to 48-52°C until dissolution was observed. The reaction mixture was then filtered into another vessel and the lines washed through with acetone (2 vol). The reaction mixture was cooled to 20-25°C before the addition of Form 1 seed crystals (0.0025wt). When crystallisation was complete the reaction mixture was cooled to 0-5°C over 1 h and stirred at 0-5°C for 30mins. The reaction mixture was heated to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was cooled to 0-5°C over 1 h and stirred at 0-5°C for 30mins.
The reaction mixture was heated to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was cooled to -12— 8°C over 3.5 h and stirred for 15 h before the product was isolated by filtration. The wet cake was washed with acetone at -10°C (2 x 3 vol) and blown dry before being unloaded. Compound A besylate was dried at ambient temperature under vacuum for 6 days with a wet nitrogen bleed to afford Form 1 . Compound A besylate was then milled. Yield: 67%
Recrystallisation of Compound A besylate anhydrate (Form 2)
Besylate salt ………………………………………………………………Besylate salt
C30H38 4O4■ C6H603S C30H38 4O4■
MW 676.83 MW 676.83
COMPOUND A besylate is charged to the vessel and treated with methyl ethyl ketone (MEK) (8vol) and water (0.35vol) and the solution heated until dissolution is observed (ca. 55-60°C). The solution is then filtered and recharged to the vessel. Pressure is then reduced to 650mbar and the reaction mixture heated further to distil out solvent. MEK is added at the same rate as solvent is removed by distillation keeping the reaction mixture volume constant. After 4 volumes of MEK have been added the reaction mixture is treated with Form 2 seed crystals (2%wt) and the distillation continued in the same manner until another 7 volumes of MEK has been added. The vacuum is then released to an atmospheric pressure of nitrogen and the temperature of the reaction mixture adjusted to 65°C. The reaction mixture is then filtered and washed with pre heated MEK (2vol at 65°C). The purified COMPOUND A besylate anhydrate is then sucked dry and dried further in a vacuum oven at 65°C at l OOmbar with a nitrogen bleed. Yield 89%
NMR data is the same for Forms 1 and 2.
1 H NMR (500MHz, DMSO-d6) 5ppm 0.71-0.80(m, 6H) 0.87-0.98(m, 1 H) 1 .31 (br. S, 1 H) 1.69(br. S, 1 H) 2.68(s, 3H) 2.69(s, 3H) 2.72-2.79(m, 1 H) 2.80-2.87(m, 1 H) 2.88-3.01 (m, 3H) 3.18-3.25(m, 1 H) 3.27-3.33(m, 1 H) 3.38-3.46(m, 1 H) 3.47-3.52(m, 1 H)3.53-3.57(m, 1 H) 3.60-3.71 (m, 3H) 3.83(dd, J=9.46,3.15 Hz, 1 H) 3.89 (br. S, 1 H)6.10(br. S, 1 H) 7.1 1 – 7.14(m, 2H) 7.19-7.23(m, 2H) 7.30-7.35(m, 3H)7.59-7.63(m, 2H) 7.67(d, J=7.25Hz, 1 H) 8.12(br. S, 1 H) 8.50(d, J=3.78Hz, 1 H)
………………………………………..
PAPER
http://pubs.acs.org/doi/abs/10.1021/jm201287w
A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3′-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pKi > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2′,6′-dimethyl-3′-pyridyl R–sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pKi = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.
(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione (69 EPELSIBAN)
 |
|
| Systematic (IUPAC) name | |
|---|---|
| (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-(morpholin-4-yl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]piperazine-2,5-dione | |
| Clinical data | |
| Legal status |
|
| Identifiers | |
| CAS number | 872599-83-2 1159097-48-9 (besylate) |
| ATC code | None |
| PubChem | CID 11634973 |
| ChemSpider | 9809717 |
| KEGG | D10117 |
| Chemical data | |
| Formula | C30H38N4O4 |
| Molecular mass | 518.6 g/mol |
| Cited Patent | Filing date | Publication date | Applicant | Title | |
|---|---|---|---|---|---|
| WO2003053443A1 | Dec 20, 2002 | Jul 3, 2003 | Glaxo Group Ltd | Substituted diketopiperazines as oxytocin antagonists | |
| WO2006000399A1 | Jun 21, 2005 | Jan 5, 2006 | Glaxo Group Ltd | Novel compounds | |
| EP2005006760W | Title not available | ||||
| US6914160 | Jul 31, 2003 | Jul 5, 2005 | Pfizer Inc | Oxytocin inhibitors | |
| US20070254888 | Jun 21, 2005 | Nov 1, 2007 | Glaxo Group Limited | Piperazinediones as Oxytocin Receptor Antagonists |
| US8202864 * | Feb 25, 2011 | Jun 19, 2012 | Glaxo Group Limited | Compounds |
| US8716286 | Oct 28, 2010 | May 6, 2014 | Glaxo Group Limited | Crystalline forms of (3R, 6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione |
| US8742099 | May 20, 2013 | Jun 3, 2014 | Glaxo Group Limited | Compounds |
| US8815856 | Mar 18, 2014 | Aug 26, 2014 | Glaxo Group Limited | Crystalline forms of (3R, 6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione |
| US20120202811 * | Apr 19, 2012 | Aug 9, 2012 | Glaxo Group Limited | Novel compounds |
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Fanetizole
Fanetizole shows immunoregulating activity.
RN: 79069-95-7
Fanetizole mesylate [USAN]
CP-48,810-27
Fanetizole mesylate
UNII-D3OG7B0G4M
Thioureas serve as a convenient starting material for 2-aminothiazoles.
Fanetizole synthesis.
Reaction of β-phenethylamine with ammonium isothiocyanate gives the corresponding thiourea. Treatment of that product with phenacyl bromide thus affords the thiazole product.[1]
| Systematic (IUPAC) name | |
|---|---|
| 4-Phenyl-N-(2-phenylethyl)-1,3-thiazol-2-amine | |
| Clinical data | |
| Legal status |
?
|
| Pharmacokinetic data | |
| Protein binding | % |
| Identifiers | |
| CAS number | 79069-94-6 |
| ATC code | ? |
| PubChem | CID 54339 |
| ChemSpider | 49083 |
| UNII | BH48F620JA |
| Chemical data | |
| Formula | C17H16N2S |
| Mol. mass | 280.39 g/mol |
………………………………………….
Journal of the Chinese Chemical Society, 2009, 56, 455-458
http://proj3.sinica.edu.tw/~chem/servxx6/files/paper_10990_1246593848.pdf
Fanetizole (3j)
mp 114-115 C (Lit.,30 116-117 C). IR (KBr) :3192, 2957, 1562, 1481, 1445, 1332, 698 cm-1;
1H NMR(CDCl3) : 2.81 (t, J = 7.4 Hz, 2H), 3.42 (dd, J = 6.8, 10.8
Hz, 2H), 6.32 (s, 1H), 6.64 (s, 1H), 7.08 (d, J = 6.8 Hz, 2H),
7.15-7.28 (m, 4H), 7.34-7.37 (m, 2H), 7.77-7.80 (m, 2H).
30=. Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron
2008, 64, 5019-5022.
…………………………………………
A remarkably high-speed solution-phase combinatorial synthesis of 2-substituted-amino-4-aryl thiazoles in polar solvents in the absence of a catalyst under ambient conditions and study of their antimicrobial activities
ISRN Organic Chemistry (2011), 434613, 6 pp. Publisher: (Hindawi Publishing Corp., )
http://www.hindawi.com/journals/isrn/2011/434613/
……………………………………………
Fanetizole
Ley et al had previously developed a tube-in-tube reactor based on a semipermeable polymer membrane to enable the transfer of gases into liquid flow streams. and here, we demonstrate the scalability and throughput of this reactor when used with ammonia gas. This was made possible by a the inclusion of a titration method to assess parameters including the liquid and gas configuration, reactor temperatures, flow rates, and solvent polarity. These data were then employed in a scaling-up process affording alkyl thioureas which were ultimately used in a telescoped procedure for the preparation of anti-inflammatory agent fanetizole on a multigram scale.
Researchers at Cambridge have shown how it is possible to calibrate a ‘tube-in-tube’ reactor containing ammonia gas using a simple in-line colourimetric titration technique.
This information was then used to deliver an ammonia solution of stoichiometrically to effect the telescoped 2 stage synthesis of the anti-inflammatory agent Fanetizole.
The automated continuous flow synthesiser was able to produce drug substance at a rate of approximately 10 g per hour, isolating the product by direct precipitation from the outflow reaction stream.
Fanetizole: Scaling-up of continuous flow processes with gases using a tube-in-tube reactor: in-line titrations and fanetizole synthesis with ammonia J. Pastre, D.L. Browne, M. O’Brien and S.V. Ley, Org. Proc. Res. Dev. 2013, 17, 1183-1191.
http://pubs.acs.org/doi/full/10.1021/op400152r
………………………..
DOI: 10.1039/B109360F…….http://pubs.rsc.org/en/content/articlelanding/2002/lc/b109360f/unauth#!divAbstract
………………………………
Bioorganic and Medicinal Chemistry Letters, 1996 , vol. 6, 12 pg. 1409 – 1414
http://www.sciencedirect.com/science/article/pii/0960894X96002417
………………………………………
ref
Heterocycles, 2010 , vol. 81, 12 pg. 2849 – 2854
Journal of the Chinese Chemical Society, 2009 , vol. 56, 3 pg. 455 – 458
Bioorganic and Medicinal Chemistry Letters, 1996 , vol. 6, 12 pg. 1409 – 1414
Pfizer Patent: DD144055DE2922523 , 1979 ;Chem.Abstr., vol. 92, 111001
Organic Process Research and Development, 2013 , vol. 17, 9 pg. 1183 – 1191
Tetrahedron, 2007 , vol. 63, 45 pg. 11066 – 11069
Tetrahedron, 2008 , vol. 64, 22 pg. 5019 – 5022
2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid
Meclinertant (SR-48692) is a drug which acts as a selective, non-peptide antagonist at the neurotensin receptor NTS1, and was the first non-peptide antagonist developed for this receptor.[1][2] It is used in scientific research to explore the interaction between neurotensin and other neurotransmitters in the brain,[3][4][5][6][7][8] and produces anxiolytic, anti-addictive and memory-impairing effects in animal studies.[9][10][11][12]
PatentSubmittedGranted1-(7-chloroquinolin-4-yl)pyrazole-3-carboxamide N-oxide derivatives, method of preparing them, and their pharmaceutical compositions [US5561234]1996-10-01
Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin [US5585497]1996-12-17
3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them [US5420141]1995-05-30
Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them [US5523455]1996-06-04
3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5607958]1997-03-04
3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5616592]1997-04-01
3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5635526]1997-06-03
Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them [US5965579]1999-10-12
| Systematic (IUPAC) name | |
|---|---|
| 2-([1-(7-Chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino)admantane-2-carboxylic acid | |
| Clinical data | |
| Legal status |
?
|
| Identifiers | |
| CAS number | 146362-70-1 |
| ATC code | ? |
| PubChem | CID 119192 |
| IUPHAR ligand | 1582 |
| UNII | 5JBP4SI96H |
| Chemical data | |
| Formula | C32H31ClN4O5 |
| Mol. mass | 587.064 |
Dr. Claudio Battilocchio, Benjamin J. Deadman, Dr. Nikzad Nikbin, Dr. Matthew O. Kitching, Prof. Ian R. Baxendale and Prof. Steven V. Ley
Article first published online: 16 APR 2013 | DOI: 10.1002/chem.201300696
Flow and pharmaceuticals? An investigation into whether machine-assisted technologies can be of true help in the multistep synthesis of a potent neurotensin receptor-1 probe, Meclinertant (SR48692; see structure), is reported.
Meclinertant (SR 48692)
We developed an improved synthesis of the neurotensin antagonist biological probe SR 48692. The preparation includes an number of chemical conversions and strategies involving the use of flow chemistry platforms which helped overcome some of the limiting synthetic transformations in the original chemical route .
Meclinertant (SR 48692): The synthesis of neurotensin antagonist SR 48692 for prostate cancer research I.R. Baxendale, S. Cheung, M.O. Kitching, S.V. Ley, J.W. Shearman Bio. Org. Med. Chem. 2013, 21, 4378-4387.
A synthesis of the neurotensin 1 receptor probe Merclinertant (SR48692) has been reported using a range of continuous flow through synthesis, in-line reaction monioring and purification techniques. This strategy has been contrasted with a more conventional batch synthesis approach.
Notably the safe use of phosgene gas (generated in situ), the superheating of solvents to accelerate reaction rates, the processing of a reagent suspension under continuous flow-through conditions and the application of semi-permeable membrane technology to facilitate work-up and purification were all techniques that could be beneficially applied in the synthetic scheme.
Abstract:
Meclinertant, Reminertant, SR-48692
The condensation of 2′,6′-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid.
EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493
…………………………….
Cilomilast (Ariflo, SB-207,499)
cas 153259-65-5
cis-{-4-cyano-4-[3- (trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-l -carboxylic acid}
cis-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-r-1-cyclohexanecarboxylic acid
C20-H25-N-O4, 343.4205
GSK….INNOVATOR
A selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease.
CLINICAL https://clinicaltrials.gov/search/intervention=Cilomilast
Cilomilast (Ariflo, SB-207,499) is a drug which was developed for the treatment of respiratory disorders such as asthma and Chronic Obstructive Pulmonary Disease (COPD). It is orally active and acts as a selective Phosphodiesterase-4 inhibitor.[1]
SB-207499 is a potent second-generation inhibitor of PDE4 (phosphodiesterase-4) with decreased side effects versus those of the well-known first-generation inhibitor, (R)-rolipram. SB-207499 is in clinical development both for asthma and chronic obstructive pulmonary disease (COPD)……..J. Med. Chem. 1998, 41, 821
Cilomilast (Ariflo™, SB 207499) is an orally active, second-generation phosphodiesterase (PDE) 4 inhibitor that is being developed by GlaxoSmithkline for the treatment of chronic obstructive pulmonary disease (COPD). The results of Phase I and Phase II studies have demonstrated that cilomilast significantly improves lung function and quality of life to a clinically meaningful extent, which has led to a comprehensive Phase III programme of research evaluating efficacy, safety and mechanism of action. However, the results of those Phase III studies are unremarkable and disappointing, raising doubt over the future of cilomilast as a novel therapy for COPD. This review summarizes data obtained from the Phase III clinical development programme, highlights some of the potential concerns both specific to cilomilast and to PDE4 inhibitors in general and assesses the likelihood that cilomilast will reach the market.
Cilomilast is GlaxoSmithKline’s selective phosphodiesterase type 4 (PDE4) inhibitor. The drug candidate had been preregistered in the U.S. for the maintenance of lung function in patients with chronic obstructive pulmonary disease (COPD) who are poorly responsive to albuterol. GlaxoSmithKline received an approval letter from the FDA in October 2003, however, in 2007, the company discontinued development of the compound. In 2008, the product was licensed to Alcon by GlaxoSmithKline for the treatment of eye disorders.
Phosphodiesterase (PDE) inhibitors, such as theophylline, have been used to treat Chronic Obstructive Pulmonary Disease (COPD) for centuries; however, the clinical benefits of these agents have never been shown to out-weigh the risks of their numerous adverse effects. Four clinical trials were identified evaluating the efficacy of cilomilast, the usual randomized, double-blind, and placebo-controlled protocols were used. It showed reasonable efficacy for treating COPD, but side effects were problematic and it is unclear whether cilomalast will be marketed, or merely used in the development of newer drugs.[2][3]
Cilomilast is a second-generation PDE4 inhibitor with antiinflammatory effects that target bronchoconstriction, mucus hypersecretion, and airway remodeling associated with COPD.
| 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid | |
| Clinical data | |
|---|---|
| Legal status |
?
|
| Identifiers | |
| CAS number | 153259-65-5 |
| ATC code | None |
| PubChem | CID 151170 |
| ChemSpider | 18826005 |
| UNII | 8ATB1C1R6X |
| Chemical data | |
| Formula | C20H25NO4 |
| Mol. mass | 343.417 g/mol |
Christensen, Siegfried B.; Guider, Aimee; Forster, Cornelia J.; Gleason, John G.; Bender, Paul E.; Karpinski, Joseph M.; Dewolf,, Walter E.; Barnette, Mary S. et al. (1998). “1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma”. Journal of Medicinal Chemistry 41 (6): 821–35. doi:10.1021/jm970090r. PMID 9526558.
The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr, trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II), which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III).
The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V), which is cyclized by means of NaH in refluxing DME, giving the 2-oxocyclohexanecarboxylic ester (VI). The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII), which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF, affording the cyclohexylidene-dithiane (IX).
The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII). Finally, this compound is hydrolyzed with KOH in methanol/THF/water.
The synthesis of SB-207499 is described. Investigation and development of new strategies for the homologation of ketone, 4-cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-cyclohexan-1-one 2 are described which produce SB-207499. Our ultimate route of synthesis to SB-207499 is robust and operationally simple and produces the final drug substance in good yield and purity.
cis-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-r-1-cyclohexanecarboxylic acid (1a):
mp 148−150 °C; IR (KBr pellet) cm–1 3300−2400, 2231, 1707, 1694;
1H (400 MHz, CDCl3) δ 11.75 (1Η, br s), 7.02 (1H, d, J = 2.3 Hz), 6.98 (1H, dd, J = 2.3, 8.4 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.82 (1H, m), 3.86 (3H, s), 2.43 (1H, tt, J = 3.7, 12.2 Hz), 2.29 (2H, br d, J = 15.6 Hz), 2.25 (2H, br d, J = 16.4 Hz), 2.05 (2H, m), 1.94 (4H, m), 1.86 (2H, m), 1.82 (2H, m), 1.64 (2H, m); 13C (100 MHz, CDCl3) δ 180.5, 149.8, 147.8, 132.8, 122.2, 117.3, 112.9, 111.9, 80.7, 56.1, 43.0, 41.7, 36.4, 32.8, 25.9, 24.0.
………………………………………..
http://www.google.com/patents/WO1995024381A1?cl=en
cis-{-4-cyano-4-[3- (trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-l -carboxylic acid} or the corresponding compounds as defined by Formula I. The preparation of any remaining compounds of the Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise:
Example 1
Preparation of cis-r4-cvano-4-(3-cyclopentyloxy-4-methoxyphenyl)cvclohexane- 1 – carboxylic acid]
1 fa (3-Cyclopentyloxy-4-methoxyphenv acetonitrile
To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilylchloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C, 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite®. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a- bromo-3-cyclopentyloxy-4-methoxy toluene in dimethylformamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (K2CO3). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to provide an off-white solid ( m.p. 32-34g C); an additional quantity of slightly impure material also was isolated. Kb Dimethyl 4-cvano-4-(‘3-cvclopentyloxy-4-methoxyphenv pimelate
To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g, 30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and the mixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) was added carefully, the reaction mixture was maintained at reflux for 5 h and then cooled. The mixture was diluted with ether, was washed once with IN hydrochloric acid and once with brine, was dried (MgSO4) and the solvent was removed in vacuo. The solid residue was triturated with 5% ethanol/hexane to provide a white solid (m.p. 81-82° C); an additional quantity was also obtained from the filtrate. Anal. (C22H29NO6) calcd: C 65.49, H 7.25, N 3.47. found: C 65.47, H 7.11, N 3.49. 1. c) 2-Caf bomethoxy-4-cvano-4-(3-cyclopentyloxy-4-methoxyphen vDcvclohexan- 1 -one To a suspension of sodium methoxide (350 mL, 1.55 mol, 25% w/w in methanol) in toluene (2.45 L) heated to 80° C under a nitrogen atmosphere was added a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (350.0 g, 0.87 mol) in toluene (1.05 L) over 10 min. The reaction was heated to 85° C by distilling away 250 mL of solvent and was vigorously stirred under nitrogen for 2 hours. The reaction was cooled to 50° C and was quenched with 3N (aq) HC1 (700 mL, 2.1 mol). The organic layer was isolated, was washed once with deionized water (700 mL) and once with brine (700 mL). The organic layer was concentrated via low vacuum distillation to afford crude 2- carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -one in toluene. This was dissolved in 4.2 L of dimethyl sulfoxide and used in the next step. 1 (d) 4-Cvano-4-f3-cyclopentyloxy-4-methoxyphenyl cvclohexan- 1-one
To a suspension of sodium chloride (315 g, 5.39 mol) and deionized water ( 315 mL) was added the dimethyl sulfoxide (4.2 L) solution of 2-carbomethoxy-4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-one ( 323 g, 0.87 mol) and the resulting suspension was heated to 155° C for 1.75 h. The reaction was cooled to 40° C, was quenched into 8 L of iced water (22 C) and was extracted with ethyl acetate (3.5 L). The aqueous layer was isolated and re-extracted with 2.5 L of ethyl acetate. The combined organic extract (6 L) was washed two times with deionized water (2 x 1 L) and once with brine (1 L). The organic layer was isolated and concentrated in vacuo to afford a residue. This residue was dissolved in refluxing isopropanol (500 mL), was cooled to 0° C and held at this temperature for 1 hour. The crystals were isolated by filtration, were washed with 250 mL of isopropanol (0° C), and were dried in a vacuum oven (45° C at 20 inches) to produce 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l -one . m.p. 111-112° C; Anal. (C19H23NO ) calcd: C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39, N 4.48. 1 (e) 2-r4-Cyano-4-G-cyclopentyloxy-4-methoxyphenyl)cvclohexylidenel- 1.3-dithiane To a solution of 2-trimethylsilyl-l,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0° C under an argon atmosphere was added rapidly n- butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78° C and a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l- one (7.53 g, 23 mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water. This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with methylene chloride, the extract was dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 10% ethyl acetate/hexanes) provided a white solid, m.p. 115-116° C. \(f) cis-r4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl‘)cyclohexane- 1 -carboxylic acidl
To a suspension of 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclo- hexylidene]-l,3-dithiane ( 140.0 g, 0.34 mol) in acetonitrile (500 mL) and deioinized water (140 mL) under nitrogen was added trifluoroacetic acid (136 g, 1.19 mol). The suspension was heated to 652 C for 1.25 h followed by the addition of 20% sodium hydroxide (420 g, 2.1 mol). The solution was heated at 70 to 75° C for an additional 1.25 h, was cooled to 45° C, deionized water (420 mL)was added followed by 3N (aq) HC1 (392 mL, 1.18 mol). The suspension was cooled to 5° C and held for 1 h. The suspension was filtered, was washed with cold (5e C) deionized water ( 200 mL), and was dried in a vacuum oven (40°C at 20 inches) to obtain crude cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid]. This material was assayed at 98.5% and was found to a 98.8:1.2 mixture of cis-to-trans isomers, which was contaminated with 0.1% of residual 1,3-propanedithiol. This material was purified via an oxidative workup as follows.
To a hot solution (65° C) of crude cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid] (85 g, 0.247 mol) in acetonitrile (425 mL) was added 1M sodium hydroxide ( 425 mL, 0.425 mol). To the solution (60° C) was added 4.25 g of calcium hypochlorite and the suspension was vigorously stirred for 2 h. The reaction was concentrated by distilling out 320 mL of solvent, followed by the addition of ethyl acetate ( 425 mL). The reaction was again concentrated by distilling out 445 mL of solvent, was cooled to 55° C followed by the addition of ethyl acetate (1.0 L) and 6N (aq.) HC1 (100 mL). The organic layer was isolated, was washed three times with deionized water (3 x 300 mL), was filtered and was concentrated by distilling out 530 mL of solvent. To the solution was added ethyl acetate (635 mL) with continued distillation to remove 750 mL of solvent. The solution was cooled to 65° C followed by the addition of hexane ( 340 mL). The suspension was cooled to 5° C, held at this temperature for 1 hour, was filtered and was washed with cold (5° C) 10% ethyl acetate/ hexane ( 200 mL). The solid was collected and was dried in a vacuum oven (40° C at 20 inches) to obtain cis- [4- cyano-4- (3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylic acid] . This material was found to contain no trans isomer. Anal.(C2θH25-Nθ4) calcd: C 69.95, H 7.34, N 4.08; found: C 69.90, H 7.35, N 4.02. Example 2
Preparation of cis-f 4-cvano-4-r3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyll- cyclohexane-1 -carboxylic acid)
2(a’) cis-F4-Cyano-4-(3-hvdroxy-4-methoxyphenvDcyclohexane- 1 -carboxylic acid]
To a solution of boron tribromide in dichlorormethane (0.1M, 335 mL, 33.5 mmol) under an argon atmosphere at -78° C was slowly added a solution of cis-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane-l -carboxylic acid] (4.03 g, 11.7 mmol) in dichloromethane (180 mL). The mixture was stirred for 5 min, 15% sodium methoxide in methanol was added to pH 8-9 and the reaction was warmed to RT. Water (lOOmL) was added and the mixture was acidified with 3N aqueous hydrochloric acid to pH 1-2. The organic layer was separated, was dried (MgSO4/Na2SO4), was filtered and was evaporated. The residue was twice dissolved in chloroform and the solution was evaporated to yield a white solid. -1H NMR(400 MHz, CDCI3) δ 7.01 (d, J=2.4 Hz, 1H), 6.96 (d of d, J=2.4, 8.5 Hz, 1H), 3.89 (s, 3H), 2.31 (m, 1H), 2.21 (br t, J=13.6 Hz, 4H), 1.98 (m,2H), 1.77 (m, 2H); mp 190-193° C. Kb) Methyl cis- r-4-cvano-4-(3-hvdroxy-4-methoxyphenyl‘)cvclohexane-l-carboxylatel -Toluenesulfonic acid monohydrate (0.015 g, 0.08 mmol) was added to a solution of the compound of Example 2(a) (0.70 g, 2.54 mmol) in dry methanol (20 mL) under an argon atmosphere and the reaction was stirred for 6 h at 45-509 C. The reaction was cooled to RT and was stirred for an additional 16 h. The solution was evaporated and the residue was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to yield the tide compound as a white solid. -1H NMR(400 MHz, CDC13) δ 7.01 (m, 2H), 6.85 (d, J=9.1 Hz, IH), 3.90 (s, 3H), 3.72 (s, 3H), 2.35 (t of t, J=3.6, 12.2 Hz, IH), 2.14-2.25 (m, 4H), 2.00 (app q, J=13.4 Hz, IH), 1.99 (app q, J=13.4 Hz, IH), 1.77 (app t, J=13.4 Hz, IH), 1.76 (app t, J=13.4 Hz, IH); mp 106-107° C.
2(c) Methyl cis- f -4-cvano-4-r3-(trans-3-hydroxycvclopentyloxy )-4-methoxyphenyl – cvclohexane- 1 -carboxylate 1
The compound of Example 2(b) (0.69 g, 2.37 mmol) was dissolved in tetrahydrofuran (20 mL) under an argon atmosphere and was treated with triphenylphosphine (1.24 g, 4.74 mmol) and cis-l,3-cyclopentanediol (0.49 g, 4.74 mmol). Diethyl azodicarboxylate (0.83 g, 4.74 mmol) was added and the mixture was stirred at RT for 16 h. The solution was evaporated, the residue was diluted with ether and the white solid was removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to yield a mixture of the title compound and triphenylphosphine oxide. The mixture was diluted with ether and the white solid triphenylphosphine oxide was removed by filtration. Evaporation of the filtrate yielded the title compound as a sticky, colorless semi-solid. 1H NMR(400 MHz, CDCI3) δ 7.07 (d, J=2.4 Hz, IH), 7.02 (d of d, J=2.4, 8.8 Hz, IH), 6.87 (d, J=8.8 Hz, IH), 4.99 (m, IH), 4.37 (m, IH), 3.85 (s, 3H), 3.74 (s, 3H), 3.16 (d, J=9.1 Hz, IH), 2.39 (m, IH), 1.88-2.25 (m, 12H), 1.80 (br t, J=13.5 Hz, 2H).
2(d) cis-f-4-cyano-4-r3-(trans-3-hydroxycyclopentyloxy )-4- methoxyphenyllcyclohexane-1 -carboxylic acid )
The compound of Example 2(c) (0.10 g, 0.27 mmol) was dissolved in 5:5:2 tetrahydrofuran methanol/water (5 mL), sodium hydroxide (0.035 g, 0.88 mmol) was added and the mixture was stirred at RT for 3 h. The solvent was evaporated, the residue was partitioned between 5% aqueous NaOH and dichloromethane and the layers were separated. The aqueous layer was acidified to pH 3 with 3N aqueous hydrochloric acid and was extracted three times with 5% methanol in chloroform. The organic extracts were combined, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 90:10:1 chloroform/methanol water) to yield a solid which was slurried in ether, was collected by filtration and was dried in vacuo to afford the title compound. MS(d/NH3) m e 377 [M + NH ]+; 1H NMR(400 MHz, CDCI3) δ 7.08 (br s, IH), 7.03 (br d, J=8.5Hz, IH), 6.88 (d, J=8.5 Hz, IH), 4.98 (m, IH), 4.38 (m, IH), 3.84 (s, IH), 2.41 (m, IH), 1.77-2.29 (m, 16H); Anal. (C2oH25NO5-»0.9 H2O) calcd: C, 63.95; H,7.19; N,3.73. found: C, 64.06; H, 6.88; N, 3.77; mp 161-163° C.
Example 3 Preparation of cis- f 4-cvano-4-r3-(cis-3-hvdroxycvclopentyloxy)-4-methoxyphenyll- cyclohexane-1 -carboxylic acid) 3(a) Methyl cis-(-4-cvano-4-r3-(cis-3-formyloxycvclopentyloxy)-4-methoxyphenyll- cvclohexane- 1 -carboxylate ) The compound of Example 2(c) (0.68 g, 1.83 mmol) was dissolved in tetrahyrofuran (20 mL) under an argon atmosphere and was treated with triphenylphosphine ( 0.96 g, 3.66 mmol) and formic acid (0.17 g, 3.66 mmol). Diethyl azodicarboxylate (0.64 g, 3.66 mmol) was added and d e mixture was stirred at RT for 16 h. The solution was evaporated, ether was added and the white solid was removed by filtration. The filtrate was concentrated and die residue was purified by flash chromatography (silica gel, 65% hexane/ethyl acetate) to yield the title compound as a clear colorless oil. **-H NMR(400 MHz, CDC13) δ 8.02 (s,lH), 7.0 (d of d, J=2.4, 8.2 Hz, IH), 6.99 (d, J=2.4 Hz, 1 H), 6.87 (d, J=8.2 Hz, IH), 5.48 (m, IH), 4.95 (m, IH), 3.84 (s, 3H), 3.72 (s, 3H), 2.31-2.40 (m, 2H), 2.13-2.28 (m, 7H), 1.96-2.06 (m, 3H), 1.74-1.87 (m, 3H).
3(h) cis- ( -4-cvano-4-r3-(cis-3-hvdroxvcvclθDentvloxy)-4-methoχyphenyllcvclohexane- 1 -carboxylic acid)
The compound of Example 3(a) (0.52 g, 1.31 mmol) was dissolved in 5:5:2 tetrahydrofuran/methanol/water (20mL), sodium hydroxide (0.32 g, 8.0 mmol) was added and die mixture was stirred at RT for 2.5 h. The solvent was evaporated and the aqueous residue was acidified to pH 1-2 with 3N aqueous hydrochloric acid. The white solid product was collected, was washed with water and was dried in vacuo to afford the title compound as a white solid. MS(CI/NH3) m/e 377 [M + NH3]+;
IH NMR(250 MHz, CDCI3) δ 6.98 (m, 2H), 6.86 (d, J=8.2 Hz, IH), 4.97 (m, IH), 4.59 (m, IH), 3.85 (s, 3H), 1.64-2.47 (m, 17H);
mp 143-145° C.
| WO1993019747A1 * | Mar 5, 1993 | Oct 14, 1993 | Siegfried B Christensen Iv | Compounds useful for treating allergic and inflammatory diseases |
| WO1993019748A1 * | Mar 5, 1993 | Oct 14, 1993 | Paul Elliot Bender | Compounds useful for treating inflammatory diseases and for inhibiting production of tumor necrosis factor |
| WO1993019750A1 * | Mar 12, 1993 | Oct 14, 1993 | Paul Elliot Bender | Compounds useful for treating allergic or inflammatory diseases |
| US4795757 * | Nov 20, 1986 | Jan 3, 1989 | Rorer Pharmaceutical Corporation | Bisarylamines |
| US5096906 * | Dec 5, 1990 | Mar 17, 1992 | University Of Virginia Alumni Patents Foundation | Method of inhibiting the activity of leukocyte derived cytokines |
| WO1993019720A2 * | Mar 12, 1993 | Oct 14, 1993 | Paul Elliot Bender | Compounds |
Foretinib (Exelixis, GlaxoSmithKline) (XL-880)
CAS No.：849217-64-7, 937176-80-2
Formula：C34H34F2N4O6
M.Wt：632.24
GSK1363089, XL880
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
Foretinib is an experimental drug candidate for the treatment of cancer.[1] It was discovered by Exelixis and is under development by GlaxoSmithKline.[2] It is currently in Phase II clinical trials.[3] As of December 2012 no phase III trials are registered.[3]
Foretinib is an inhibitor of the kinase enzymes c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2).[4]
Foretinib is an orally bioavailable small molecule with potential antineoplastic activity. MET/VEGFR2 inhibitor GSK1363089 binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers. VEGFR2 is found on endothelial and hematopoietic cells and mediates the development of the vasculature and hematopoietic cells through VEGF signaling.
Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.
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| Patent | Submitted | Granted |
|---|---|---|
| Preparation of a Quinolinyloxydiphenylcyclopropanedicarboxamide [US2010081805] | 2010-04-01 | |
| C-Met Modulators and Method of Use [US2012022065] | 2012-01-26 | |
| C-Met Modulators and Method of Use [US2011077233] | 2011-03-31 | |
| c-Met modulators and methods of use [US7579473] | 2009-07-02 | 2009-08-25 |
| c-MET MODULATORS AND METHODS OF USE [US8067436] | 2009-04-23 | 2011-11-29 |
| C-MET MODULATORS AND METHOD OF USE [US8178532] | 2007-09-27 | 2012-05-15 |
| Method of Treating Cancer using a cMet and AXL Inhibitor and an ErbB Inhibitor [US2009274693] | 2009-11-05 | |
| c-MET MODULATORS AND METHOD OF USE [US2007244116] | 2007-10-18 | |
| c-Met modulators and methods of use [US2007054928] | 2007-03-08 |
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http://www.google.com/patents/WO2014067417A1?cl=en
Foretinib (GSK1363089, XL880) quinoline compounds are, an oral c-Met and VEGFR / KDR kinase inhibitor of c-Met kinase and KDR kinase IC 5Q Wo port respectively 0.4 0.8 nM, the current has entered Phase II clinical study (WO2010036831Al). Clinical studies have shown that, Foretinib variety of people, such as human lung cancer cells, human gastric cancer cells and other tumor cell lines showed a significant inhibitory effect, an IC 50 value of 0.004 g / mL.
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http://www.google.com/patents/WO2014145693A1?cl=en
Accordingly, small-molecule compounds that specifically inhibit, regulate, and/or modulate the signal transduction of kinases, particularly including Ret, c-Met, and VEGFR2 described above, are particularly desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. One such small-molecule is XL880, known variously as N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide and alternatively as foretimb. Foretimb has the chemical structure:
[0007] WO 2005/030140 describes the synthesis of foretinib (Example 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate, and/or modulate the signal transduction of kinases (Assays, Table 4, entry 312). Example 44 begins at paragraph [0349] in WO 2005/030140.
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Scheme 2
Preparation of 4-Chloro-6,7-dimethoxy-quinoIine
[00173] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).
Preparation of -(6, 7 -Dimethoxy-quinoline- -yloxy)-phenylamine
[00174] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 21 1.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg). Alternative Preparation of 4-(6, 7-Dimethoxy-quinoIine-4-yloxy)-phenylamine
[00175] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenoI (30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a reactor, followed by N(N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated to 105-1 15 °C for approximately 9 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-25 °C and water (315 kg) was added over a two hour period while maintaining the temperature between 20-30 °C. The reaction mixture was then agitated for an additional hour at 20-25 °C. The crude product was collected by filtration and washed with a mixture of 88kg water and 82.1 kg DMA, followed by 175 kg water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1 percent w/w.
[00176] In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used and the reaction temperature was increased from 1 10-120 °C. In addition , the cool down temperature was increased to 35-40 °C and the starting temperature of the water addition was adjusted to 35-40 °C, with an allowed exotherm to 45 °C.
Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
[00177] Triethylamine (19.5 kg) was added to a cooled (approximately 5 °C) solution of cyclopropane-l,l-dicarboxylic acid (24.7 kg) in THF (89.6 kg) at a rate such that the batch temperature did not exceed 5 °C. The solution was stirred for approximately 1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, the solution was stirred for approximately 4 hours keeping temperature below 10 °C. A solution of 4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 10 hours after which the reaction was deemed complete. The reaction mixture was then diluted with isopropyl acetate (218.1 kg). This solution was washed sequentially with aqueous sodium hydroxide (10.4 kg, 50 percent dissolved in 1 19 L of water) further diluted with water (415 L), then with water (100 L) and finally with aqueous sodium chloride (20.0 kg dissolved in 100 L of water). The organic solution was concentrated by vacuum distillation (100 L residual volume) below 40 °C followed by the addition of n- heptane (171.4 kg), which resulted in the precipitation of solid. The solid was recovered by filtration and washed with n-heptane ( 102.4 kg), resulting in wet, crude l-(4-fluoro- phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). The crude, l-(4-fluoro- phenylcarbamoy -cyclopropanecarboxylic acid was dissolved in methanol (139.7 kg) at approximately 25 °C followed by the addition of water (320 L) resulting in slurry which was recovered by filtration, washed sequentially with water (20 L) and n-heptane (103.1 kg) and then dried on the filter at approximately 25 °C under nitrogen to afford the title compound (25.4 kg).
Preparation of l-(4-Fluoro-phenyIcarbamoyl)-cyclopropanecarbonyl chloride
[00178] Oxalyl chloride ( 12.6 kg) was added to a solution of I -(4-fluoro- phenylcarbamoyD-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25 °C. This solution was used in the next step without further processing.
Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride
[00179] A reactor was charged with l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175kg THF. The reaction mixture was adjusted to 12-17 °C and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12-17 °C for 3 to 8 hours. This solution was used in the next step without further processing.
Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide
[00180] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 °C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 °C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 °C and then at approximately 45 °C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD). Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoIine-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide
[00181] A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a solution of 48.3 K2C03 in 169 kg water. The acid chloride solution of described in the
Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cvclopropanecarbonyl chloride above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine while maintaining the temperature between 20-30 °C over a minimum of two hours. The reaction mixture was stirred at 20-25 °C for a minimum of three hours. The reaction temperature was then adjusted to 30-25 °C and the mixture was agitated. The agitation was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added 804 kg water. The reaction was left stirring at 15-25 °C for a minimum of 16 hours.
[00182] The product precipitated. The product was filtered and washed with a mixture of 179 kg water and 157.9 kg THF in two portions. The crude product was dried under a vacuum for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30-35 °C for approximately 30 minutes. 456 kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol denatured with methanol over two hours. The mixture was agitated at 15-25 °C fir at least 16 hours. The product was filtered and washed with a mixture of 143 kg water and 126.7 THF in two portions. The product was dried at a maximum temperature set point of 40 °C.
[00183] In an alternative procedure, the reaction temperature during acid chloride formation was adjusted to 10-15 °C. The recrystallization temperature was changed from 15-25 °C to 45-50 °C for 1 hour and then cooled to 15-25 °C over 2 hours.
Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide, malate salt
[00184] Cyclopropane- 1 , 1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1 133.2 kg) (approximate residual volume 71 1 L; KF < 0.5 % w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).
Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yIoxy)-phenyl]-amide (4-fluoro-phenyI)-amide, (L) malate salt
[00185] Cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor and the mixture was heated 50-55 °C for approximately 1-3 hours, and then at 55-60 °C for an addition al 4-5 hours. The mixture was clarified by filtration through a 1 μπι cartridge. The reactor temperature was adjusted to 20-25 °C and vacuum distilled with a vacuum at 150-200 mm Hg with a maximum jacket temperature of 55 °C to the volume range of 558-731 L.
[00186] The vacuum distillation was performed two more times with the charge of 380 kg and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the batch was adjusted to 18 v/w of cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide by charging 159.9 kg methyl ethyl ketone to give a total volume of 880L. An addition al vacuum distillation was carried out by adjusting 245.7 methyl ethyl ketone. The reaction mixture was left with moderate agitation at 20-25 °C for at least 24 hours. The product was filtered and washed with 415.1 kg methyl ethyl ketone in three portions. The product was dried under a vacuum with the jacket temperature set point at 45 °C.
[00187] In an alternative procedure, the order of addition was changed so that a solution of 17.7 kg L-malic acid dissolved in 129.9 kg water was added to cyclopropane- 1,1- dicarboxylic acid [4-(6,7-dimethoxy-quinoHne-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)- amide (48.7 kg) in methyl ethyl ketone (673.3 kg).
Preparation of Compound 2
[00188] Compound 2 was prepared as provided in Scheme 3 and the accompanying experimental examples. Scheme 3
Toluene
[00189] In Scheme 1, Xb is Br or CI. For the names of the intermediates described within the description of Scheme 1 below, Xb is referred to as halo, wherein this halo group for these intermediates is meant to mean either Br or CI.Preparation of l-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone
[00190] Water (70 L) was charged to the solution of l-[4-(3-halo propoxy)- 3-methoxy phenyl] ethanone (both the bromo and the chloro compound are commercially available). The solution was cooled to approximately 4 °C. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch temperature did not exceed approximately 18 °C. The resulting solution was cooled to approximately 5 °C and 70 percent nitric acid (75.8 kg) was added at a rate such that the batch temperature did not exceed approximately 10 °C. Methylene chloride, water and ice were charged to a separate reactor. The acidic reaction mixture was then added into this mixture. The methylene chloride layer was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride layers were washed with aqueous potassium bicarbonate solution and concentrated by vacuum distillation. 1- Butanol was added and the mixture was again concentrated by vacuum distillation. The resulting solution was stirred at approximately 20°C during which time the product crystallized. The solids were collected by filtration, washed with 1-butanol to afford compound the title compound, which was isolated as a solvent wet cake and used directly in the next step. ‘HNMR (400MHz, DMSO-d6): δ 7.69 (s, 1H), 7.24 (s, 1H); 4.23 (m, 2H), 3.94 (s, 3H), 3.78 (0-3.65 (t) (2H), 2.51 (s, 3H), 2.30-2.08 (m, 2H) LC/MS Calcd for [M(CI)+H]+ 288.1, found 288.0; Calcd for [M(Br)+H]+ 332.0, 334.0, found 331.9, 334.0.
Preparation of l-[5-methoxy-4-(3-morpholin-4-yl-propoxy)-2-nitro-phenyl]-ethanone
[00191] The solvent wet cake isolated in the previous step was dissolved in toluene. A solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) was added to this solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The resulting 2 phase mixture was heated to approximately 85°C for about 9 hours. The mixture was then cooled to ambient temperature. The organic layer was removed. The aqueous layer was back extracted with toluene. The combined toluene layers were washed sequentially with two portions of saturated aqueous sodium thiosulfate followed by two portions of water. The resulting solution of the title compound was used in the next step without further processing. ‘HNMR (400MHz, DMSO-d6): δ 7.64 (s, 1 H), 7.22 (s, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.57 (t, 4H), 2.52 (s, 3H), 2.44-2.30 (m, 6H), 1.90 (quin, 2H); LC/MS Calcd for [M+H]+ 339.2, found 339.2.
Preparation of l-[2-amino-5-methoxy-4-(3-morpholin-4-yl- propoxy)-phenyl]-ethanone
[00192] The solution from the previous step was concentrated under reduced pressure to approximately half of the original volume. Ethanol and 10 percent Pd C (50 percent water wet, 5.02 kg) were added; the resulting slurry was heated to approximately 48 °C and an aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. When the addition was complete and the reaction deemed complete by thin layer chromatography (TLC), water was added to dissolve the by-product salts. The mixture was filtered to remove the insoluble catalyst. The filtrate was concentrated under reduced pressure and toluene was added. The mixture was made basic (pH of about 10) by the addition of aqueous potassium carbonate. The toluene layer was separated and the aqueous layer was back extracted with toluene. The combined toluene phases were dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting solution was used in the next step without further processing. ‘HNMR (400MHZ, DMSO-d6): δ 7.1 1 (s, 1H)„ 7.01 (br s, 2H), 6.31 (s, 1H), 3.97 (t, 2H), 3.69 (s, 3H), 3.57 (t, 4H), 2.42 (s, 3H), 2.44-2.30 (m, 6H), 1.91 (quin, 2H LC/MS Calcd for [M+H]+ 309.2, found 309.1.
Preparation of 6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoiin- 4-ol, sodium salt
[00193] A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg) was added to the solution from the previous step. The mixture was warmed to approximately 44 °C for about 3 hours. The reaction mixture was cooled to approximately 25°C. Methyl t- butyl ether (MTBE) was added which caused the product to precipitate. The product was collected by filtration and the cake was washed with MTBE and dried under reduced pressure at ambient temperature. The dried product was milled through a mesh screen to afford 60.2 kg of the title compound. ‘HNMR (400MHz, DMSO-d6): δ 1 1.22 (br s, 1H), 8.61 (d, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.17 (d, 1H), 4.29 (t, 2 H), 3.99 (m, 2H), 3.96 (s, 3H), 3.84 (t, 2H), 3.50 (d, 2H), 3.30 (m, 2H), 3.1 1 (m, 2H), 2.35 (m, 2H), LC/MS Calcd for [M+H]+ 319.2, found 319.1.
Preparation of 4-chIor-6-methoxy-7-(3 morpholin-4-yl)-quinoline
[00194] Phosphorous oxychloride (26.32 kg) was added to a solution of 6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ol (5.00 kg) in acetonitrile that was heated to 50-55 °C. When the addition was complete, the mixture was heated to reflux (approximately 82 °C) and held at that temperature, with stirring for approximately 18 hours at which time it was sampled for in process HPLC analysis. The reaction was considered complete when no more than 5 percent starting material remained. The reaction mixture was then cooled to 20-25 °C and filtered to remove solids. The filtrate was then concentrated to a residue. Acetronitrile was added and the resulting solution was concentrated to a residue. Methylene chloride was added to the residue and the resulting solution was quenched with a mixture of methylene chloride and aqueous ammonium hydroxide. The resulting 2 phase mixture was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride solutions were dried over anhydrous magnesium sulfate, filtered and concentrated to a solid. The solids were dried at 30-40 °C under reduced pressure to afford the title compound (1.480 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.21 (t, 2 H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97 (quin, 2H) LC MS Calcd for [M+Hf 458.2, found 458.0.
Preparation of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morphoIin-4-yl
propoxy)quinoline
[00195] A solution of 4-chIoro-6-methoxy-7-(3 morpholin-4-yl)-quinoline (2.005 kg, 5.95 mol) and 2 fluoro-4-nitrophenol (1.169 kg, 7.44 mol) in 2,6-Iutidine was heated to 140-145 °C, with stirring, for approximately 2 hours, at which time it was sampled for in process HPLC analysis. The reaction was considered complete when less than 5 percent starting materia! remained. The reaction mixture was then cooled to approximately 75 °C and water was added. Potassium carbonate was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, washed with aqueous potassium carbonate, and dried at 55-60 °C under reduced pressure to afford the title compound (1.7 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.54 (d, 1H), 8.44 (dd, 1H), 8.18 (m, 1H), 7.60 (m, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 6.75 (d, 1H), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H]+ 337.1 , 339.1 , found 337.0, 339.0.
Preparation of 3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yIoxy]- phenylamine
[00196] A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4- yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20-25 °C for approximately 1 hour. The solids were collected by filtration, washed with water and dried at 50-60 °C under reduced pressure to afford the title compound (1.164 kg)._’H NMR (400MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for
[M+H]+ 428.2, found 428.1.
Preparation of l-(4-fluoro-phenylcarbamoyl)-cycIopropanecarboxylic acid
[00197] Triethylamine (7.78 kg) was added to a cooled (approximately 4°C) solution of commercially available cyclopropanel.l-dicarboxylic acid (9.95 kg) in THF, at a rate such that the batch temperature did not exceed 10 °C. The solution was stirred for approximately 30 minutes and then thionyl chloride (9.14 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, a solution of 4 fluoroaniline (9.4 kg) in THF was added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate. The diluted solution was washed sequentially with aqueous sodium hydroxide, water, and aqueous sodium chloride. The organic solution was concentrated by vacuum distillation. Heptane was added to the concentrate. The resulting slurry was filtered by centrifugation and the solids were dried at approximately 35 °C under vacuum to afford the title compound (10.2 kg). Ή NMR (400 MHz, DMSO-d6): δ 13.06 (br s, 1H), 10.58 (s, 1H), 7.65-7.60 (m, 2H), 7.18-7.12 (m, 2H), 1.41 (s, 4H), LC/MS Calcd for [M+H]+ 224.1 , found 224.0.
Preparation of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride
[00198] Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5°C) solution of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10°C. When the addition was complete, the batch was allowed to warm to ambient temperature and held with stirring for approximately 2 hours, at which time in process HPLC analysis indicated the reaction was complete. The solution was used in the next step without further processing.
Preparation of cyclopropane-l,l-dicarbox lic acid {3-fluoro-4-[6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluorophenyl)-amide
[00199] The solution from the previous step was added to a mixture of 3-fluoro-4-[6- methoxy-7-(3-mo holin-4-yl-propox )-quinolin-4-ylo y]-phenylamine (1 160 kg) and potassium carbonate (412.25 g) in THF and water at a rate such that the batch temperature was maintained at approximately 15-21 °C. When the addition was complete, the batch was warmed to ambient temperature and held with stirring for approximately 1 hour, at which time in process HPLC analysis indicated the reaction was complete. Aqueous potassium carbonate solution and isopropyl acetate were added to the batch. The resulting 2-phase mixture was stirred and then the phases were allowed to separate. The aqueous phase was back extracted with isopropyl acetate. The combined isopropyl acetate layers were washed with water followed by aqueous sodium chloride and then slurried with a mixture of magnesium sulfate and activated carbon. The slurry was filtered over Celite® and the filtrate was concentrated to an oil at approximately 30°C under vacuum to afford the title compound which was carried into the next step without further processing. Ή NMR (400MHz, DMSO- d6): δ 10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (m, 2H), 7.16 (t, 2H), 6.41 (d, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H), 1.47 (m, 4H). LC MS Calcd for [M+H]+ 633.2, found 633.1.
Preparation of the bisphosphate salt of cyclopropane-l,l-dicarboxylic acid {3-fluoro-4- [6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide (4-fluoro- phenyl)-amide
[00200] Cyclopropane- 1,1-dicarboxy lie acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluoro phenyl)-amide from the previous step was dissolved in acetone and water. Phosphoric acid (85%, 372.48 g) was added at a rate such that the batch temperature did not exceed 30 °C. The batch was maintained at approximately 15- 30 °C with stirring for 1 hour during which time the product precipitated. The solids were collected by filtration, washed with acetone and dried at approximately 60 °C under vacuum to afford the title compound (1.533 kg). The title compound has a c-Met IC50 value of less than 50 nM. The bisphosphate salt is not shown in scheme 1. Ή NMR (400
MHz, DMSO-d6): (diphosphate) δ 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1 H), 7.93 (dd, 1H), 7.65 (m, 2H), 7.53 (d, 2H), 7.42 (m, 2H), 7.17 (m, 2H), 6.48 (d, 1H), 5.6 (br s, 6H), 4.24 (t, 2H), 3.95 (s, 3H), 3.69 (bs, 4H), 2.73 (bs, 6H), 2.09 (t, 2H), 1.48 (d, 4H).
| Foretinib | |
|---|---|
 |
|
| Identifiers | |
| CAS number | 849217-64-7 |
| ChemSpider | 24608641 |
| UNII | 81FH7VK1C4 |
| Jmol-3D images | Image 1 |
| Properties | |
| Molecular formula | C34H34F2N4O6 |
| Molar mass | 632.65 g mol−1 |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa) | |
| CN102227164A * | Sep 25, 2009 | Oct 26, 2011 | 葛兰素史密斯克莱有限责任公司 | Preparation of quinolinyloxydiphenylcyclopropanedicarboxamide |
| CN102977014A * | Nov 5, 2012 | Mar 20, 2013 | 沈阳药科大学 | New quinoline compounds and uses thereof |
| Reference | ||
|---|---|---|
| 1 | * | BAOHUI QI ET AL.: ‘Discovery and optimization of novel 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazones as c-Met Kinase Inhibitors.‘ BIOORGANIC & MEDICINAL CHEMISTRY. vol. 21, 19 June 2013, pages 5246 – 5260 |
| 2 | * | BAOHUI QI ET AL.: ‘Synthesis and Biological Evaluation of 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazone Scaffolds as Selective c-Met Inhibitors.‘ ARCH. PHARM. CHEM. LIFE SCI. vol. 346, no. 8, 2013, pages 596 – 609 |
Bafetinib
4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide, cas 859212-16-1
4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide
859212-07-0 (hydrochloride)
Bafetinib , previously as INNO-406 , NS-187 and CNS-9 refers is an experimental drug from the substance group ofbenzamides , who as Tyrosinkinasehemmstoff to be used. [2] It was originally developed by the Japanese company Nippon Shinyaku and 2006 Innovive Pharmaceuticals licensed. [3] Innovive was established in June 2008 by the CytRx Corp. adopted. [4]
Bafetinib, also known as INNO-406, is an orally bioavailable 2-phenylaminopyrimidine derivative with potential antineoplastic activity. Bafetinib specifically binds to and inhibits the Bcr/Abl fusion protein tyrosine kinase, an abnormal enzyme produced by Philadelphia chromosomal translocation associated with chronic myeloid leukemia (CML). This agent also inhibits the Src-family member Lyn tyrosine kinase, upregulated in imatinib-resistant CML cells and in a variety of solid cancer cell types. The inhibitory effect of bafetinib on these specific tyrosine kinases may decrease cellular proliferation and induce apoptosis in tumor cells that overexpress these kinases. CML patients may be refractory to imatinib, which sometimes results from point mutations occurring in the kinase domain of the Bcr/Abl fusion product. Due to its dual inhibitory activity, the use of bafetinib has been shown to overcome this particular drug resistance.
INNO-406 (formerly NS-187) is a potent, orally available, rationally designed, dual Bcr-Abl and Lyn kinase inhibitor that is currently in early clinical studies at CytRx Oncology for the treatment of B-cell chronic lymphocytic leukemia, metastatic prostate cancer and glioblastoma multiforme. CytRx is also conducting phase I clinical studies for the treatment of recurrent high-grade glioma or metastatic disease to the brain that has progressed after treatment with whole brain radiation therapy or stereotactic radiosurgery.
The company is developing INNO-406 in preclinical studies for the prevention of bone loss in multiple myeloma patients. Nippon Shinyaku is also evaluating the compound for the treatment of chronic myeloid leukemia. The compound had been under evaluation for the treatment of certain forms of acute myeloid leukemia (AML) that are refractory or intolerant of other approved treatments; however, no recent development has been reported for this indication.
Based on its mechanisms of action, INNO-406 is expected to be effective in treating Gleevec-resistant CML and may delay or even prevent the onset of resistance in treatment naive CML patients. The ability of INNO-406 to specifically target the Bcr-Abl and Lyn kinases may result in a better side effect profile than compounds that target multiple kinases such as a pan-Src inhibitor.
In 2005, the compound was licensed to Innovive Pharmaceuticals (acquired by CytRx Oncology in 2008) by Nippon Shinyaku on a worldwide basis, with the exception of Japan, for the treatment of CML. Orphan drug designation was assigned to the compound for the treatment of CML in the U.S in 2007 and in the E.U. in 2010.
Bafetinib is an inhibitor of tyrosine kinases . It affects the formation of the fusion protein Bcr-Abl , as well as that of theenzyme Lyn kinase and should in mice ten times stronger effect than the imported Tyrosinkinasehemmstoff imatinib .[5]
| Patent | Submitted | Granted |
|---|---|---|
| Amide Derivative and Medicine [US7728131] | 2008-11-27 | 2010-06-01 |
Bafetinib currently has no indication for an authorization as medicines .
The drug is intended for the treatment of chronic lymphocytic leukemia are developed (CLL). For this indication is Bafetinib is in the development phase II (June 2011). [6]
Bafetinib is also in phase II for the treatment of hormone-refractory prostate cancer . [7]
The US regulatory authority FDA had Bafetinib end of 2006, the status of a drug orphan (orphan drug) awarded. [8]This status could allow an accelerated development and approval.
N-[3-([5,5′-Bipyrimidin]-2-ylamino)-4-methylphenyl]-4-[[(3S)-3-(dimethyl-amino)-1-pyrrolidinyl]methyl]-3-(trifluoromethyl)benzamide
CAS No .: 887650-05-7
MW: 576.62
Formula: C 30 H 31 F 3 N 8 O
Synonym: INNO-406, NS-187
4-(bromomethyl)-3-trifluoromethylbenzoic acidTo 60.0 g of 4-methyl-3-trifluoromethylbenzoic acid was added 600 ml of isopropyl acetate. Under stirring at room temperature, a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water were added in turn. The mixture was gradually heated from 30° C. up to 50° C. at intervals of 10° C. and stirred until the color of the reaction solution disappeared. The aqueous layer was separated to remove, and to the organic layer were added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and then the mixture was gradually heated up to 60° C. as above. After separation, to the organic layer were further added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and the mixture was gradually heated as above and heated to the temperature the mixture was finally refluxed. After the completion of the reaction, the reaction solution was separated, the organic layer was washed twice with a 5% aqueous sodium thiosulfate solution and twice with 15% saline, dried over anhydrous magnesium sulfate, and, then the solvent was distilled off under reduced pressure. To the residue was added 120 ml of n-heptane, the mixture was stirred, and then the crystals were collected by filtration to obtain 50.0 g of the objective compound as colorless crystals.
Melting point: 140-143° C.
Step 2
4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide7.69 g of 4-(bromomethyl)-3-trifluoromethylbenzoic acid obtained in the step 1 was suspended in 154 ml of anhydrous dichloromethane. Under ice-cool stirring, 6.59 ml of oxalyl chloride and 0.1 ml of anhydrous N,N-dimethylformamide were added dropwise. Under ice cooling, the mixture was further stirred for 3 hours, and then the reaction solution was concentrated under reduced pressure. To the residue was added 70 ml of anhydrous 1,4-dioxane, and then 7.00 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) and 4.18 g of potassium carbonate were added in turn, followed by stirring at room temperature for 18 hours. To the reaction solution was added 175 ml of water, and the mixture was violently stirred for one hour. Then, the deposit was collected by filtration and washed in turn with water, a small amount of acetonitrile, ethyl acetate and diisopropyl ether to obtain 8.10 g of the objective compound as pale yellow crystals.
Melting point: 198-202° C. (with decomposition)
To a solution of 6.00 g of 4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide (Reference Example 31) in 60 ml of anhydrous N,N-dimethylformamide were added 1.51 g of (S)-(−)-3-(dimethylamino)pyrrolidine and 1.83 g of potassium carbonate, followed by stirring at room temperature for 14 hours. To the reaction solution were added water and an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.57 g of pale yellow crystals.
Melting point: 179-183° C. (with decomposition)
A series of 3-substituted benzamide derivatives of STI-571 (imatinib mesylate) was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. Several 3-halogenated and 3-trifluoromethylated compounds, including NS-187, showed excellent potency.
Reagents and conditions: (a) NaBrO3, NaHSO3, EtOAc; (b) (COCl)2, cat. DMF, CH2Cl2, rt; (c) 7, K2CO3, dioxane, rt; (d) cyclic amines, K2CO3, DMF, rt.
………………………………
Bioorganic and Medicinal Chemistry Letters, 2007 , vol. 17, 10 pg. 2712 – 2717
Bafetinib|
References |
1: Peter B, Hadzijusufovic E, Blatt K, Gleixner KV, Pickl WF, Thaiwong T, Yuzbasiyan-Gurkan V, Willmann M, Valent P. KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406). Exp Hematol. 2010 Sep;38(9):782-91. doi: 10.1016/j.exphem.2010.05.004. Epub 2010 May 26. PubMed PMID: 20685234.
2: Kantarjian H, le Coutre P, Cortes J, Pinilla-Ibarz J, Nagler A, Hochhaus A, Kimura S, Ottmann O. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer. 2010 Jun 1;116(11):2665-72. doi: 10.1002/cncr.25079. PubMed PMID: 20310049; PubMed Central PMCID: PMC2876208.
3: Rix U, Remsing Rix LL, Terker AS, Fernbach NV, Hantschel O, Planyavsky M, Breitwieser FP, Herrmann H, Colinge J, Bennett KL, Augustin M, Till JH, Heinrich MC, Valent P, Superti-Furga G. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia. 2010 Jan;24(1):44-50. doi: 10.1038/leu.2009.228. Epub 2009 Nov 5. PubMed PMID: 19890374.
4: Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 2008 Nov;15(11):1712-22. doi: 10.1038/cdd.2008.107. Epub 2008 Jul 11. PubMed PMID: 18617896.
5: Morinaga K, Yamauchi T, Kimura S, Maekawa T, Ueda T. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification. Int J Cancer. 2008 Jun 1;122(11):2621-7. doi: 10.1002/ijc.23435. PubMed PMID: 18338755.
6: Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y, Maekawa T. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res. 2008 Jun;32(6):980-3. doi: 10.1016/j.leukres.2007.11.008. Epub 2008 Jan 8. PubMed PMID: 18191450.
7: Pan J, Quintás-Cardama A, Manshouri T, Cortes J, Kantarjian H, Verstovsek S. Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406. Cancer Sci. 2007 Aug;98(8):1223-5. Epub 2007 May 22. PubMed PMID: 17517053.
8: Kuroda J, Kimura S, Strasser A, Andreeff M, O’Reilly LA, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Tabe Y, Taniwaki M, Maekawa T. Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ. 2007 Sep;14(9):1667-77. Epub 2007 May 18. PubMed PMID: 17510658.
9: Maekawa T. [Innovation of clinical trials for anti-cancer drugs in Japan–proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia]. Gan To Kagaku Ryoho. 2007 Feb;34(2):301-4. Japanese. PubMed PMID: 17301549.
10: Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights. 2007 Nov 14;2:93-106. PubMed PMID: 19662183; PubMed Central PMCID: PMC2716809.
11: Yokota A, Kimura S, Masuda S, Ashihara E, Kuroda J, Sato K, Kamitsuji Y, Kawata E, Deguchi Y, Urasaki Y, Terui Y, Ruthardt M, Ueda T, Hatake K, Inui K, Maekawa T. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood. 2007 Jan 1;109(1):306-14. Epub 2006 Sep 5. PubMed PMID: 16954504.
Bafetinib in its binding site
Bafetinib
New Drug Approvals 