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CDK Inhibitor, MK 7965, DINACICLIB, SCH 727965
REVIEW…….http://www.mdpi.com/2072-6694/6/4/2224/htm
One of the most popular CDK inhibitor in clinical trials in the recent years was dinaciclib (MK-7965, SCH 727965) (Figure 3), the inhibitor of CDK1, CDK2, CDK5, and CDK9. A Phase I trial on the effect of dinaciclib in combination with aprepitant was performed in patients with advanced malignancies [44]. Aprepitant is used for the prevention of chemotherapy-induced nausea and vomiting, is known as an inhibitor and inducer of CYP3A4, which metabolizes dinaciclib.
Coadministration of dinaciclib with aprepitant resulted in no clinically significant effect on the pharmacokinetics and did not alter the safety profile of dinaciclib. The first Phase I clinical trial on dinaciclib as a single agent was performed on patients with advanced malignancies [68]. Forty-eight patients with various solid tumors were treated and 10 of them achieved prolonged stable disease for at least four treatment cycles. Adverse effects were mild, the most common being nausea, anemia, decreased appetite and fatigue.
A phase II multi-center study of dinaciclib for relapsed and/or refractory AML was performed on 20 patients [69]. Temporary decrease in peripheral blood and/or bone marrow blasts was observed in 60% of patients. Four of 13 (31%) patients with circulating blasts had >50% decrease and 6 (46%) >80% decrease in the absolute blast count within 1–8 days of the first dinaciclib dose. Toxicities included diarrhea, fatigue, transaminitis, and manifestations of tumor lysis syndrome, with one patient who deceased of acute renal failure. Another Phase II study was performed of dinaciclib versus erlotinib in patients with non-small cell lung cancer [70].
Unfortunately, it was found that dinaciclib was not successful as monotherapy in non-small cell lung cancer. Most common toxicities included neutropenia, leukopenia, vomiting, and diarrhea. Yet another Phase II study was performed on dinaciclib versus capecitabine in patients with advanced breast cancer [71]. Dinaciclib treatment demonstrated antitumor activity in two of seven patients with ER-positive and ERBB 2-negative metastatic breast cancer, however efficacy was not superior to capecitabine (p = 0.991).
Toxicities included neutropenia, leukopenia, increase in aspartate aminotransferase, and febrile neutropenia. Phase I nonrandomized dose-escalation trial was performed, where patients with relapsed or refractory chronic lymphocytic leukemia were treated with dinaciclib and rituximab [72]. Four out of six patients achieved stable disease, and one patient achieved complete response. Drug-related adverse events were mostly hematological, digestive and metabolic and no dose-limiting toxicities were observed. Dinaciclib was also moved into Phase III development for refractory chronic lymphocytic leukemia [73]. Phase I/II clinical trial Dinaciclib in patients with relapsed multiple myeloma showed promise as single agent [74]. The overall confirmed response rate was 3 of 27 (11%). Adverse effects included leukopenia, thrombocytopenia, gastrointestinal symptoms, alopecia, and fatigue. –
FOR REF See more at: http://www.mdpi.com/2072-6694/6/4/2224/htm#sthash.amBuLwq1.dpuf
Dinaciclib (SCH-727965) is an experimental drug that inhibits cyclin-dependent kinases (CDKs.[1] It is being evaluated in clinical trials for various cancer indications.[2]
 |
|
| Systematic (IUPAC) name | |
|---|---|
| (S)-3-(((3-Ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)pyridine 1-oxide | |
| Clinical data | |
| Legal status |
|
| Identifiers | |
| CAS number | 779353-01-4 |
| ATC code | ? |
| PubChem | CID 46926350 |
| ChemSpider | 25027387 |
| ChEMBL | CHEMBL2103840 |
| Synonyms | SCH-727965 |
| Chemical data | |
| Formula | C21H28N6O2 |
http://www.google.com.tr/patents/US8076479
One example of these inhibitors is the compound of Formula II.
The synthesis of the compound of Formula II is described in the ‘878 publication according to Scheme II:
Scheme II:
Step 1—Amidization to Form Substituted Pyrazole
http://www.google.com.tr/patents/US8076479
Step 2—Formation and Dehalogenation of pyrazolo[1,5a]pyrimidine
Step 3—Amination (Two Separate, Sequential Reactions)
As described in the ‘878 publication, Synthetic Scheme II leading to the compound of Formula II has several disadvantages from the standpoint of commercial scale synthesis. In step 1, the starting material (compound “C”) used in the formation of compound “D” is a sticky, viscous oil which is difficult to process (weigh, transfer, and blend). Moreover, step 1, as described in the ‘878 publication, requires isolation and chromatographic purification of compounds C and D prior to carrying out each subsequent derivatization reaction. In addition, as described in the ‘878 publication, the reaction of compound C with malonate diester is carried out using the diester as a solvent. After isolation and purification of the resultant malonate adduct, compound D, ring closure to form diketone compound E is carried out in methanol. In accordance with the procedure described in the ‘878 publication, compound E is isolated and dried, then converted to the corresponding dichloride in N,N-dimethyl aniline by treatment with phosphorous oxychloride (POCl3). The dichloride thus formed was isolated and purified by chromatography prior to the sequential amination reactions. Additionally, the compounds of Formula G and of Formula II require chromatography purification and isolations, as described in the ‘878 publication.
As further described in the ‘878 publication, each of the amination reactions were run separately with isolation and chromatographic purification between amination reactions. Accordingly, the ‘878 publication describes the preparation of the compound of Formula II utilizing a scheme consisting of five separate reaction steps with intervening isolation and purification of the products, each sequential step being carried out in a different solvent system. The overall yield of the compound of Formula II reported for this synthesis, based on starting compound C (Scheme II) is about 20%.
Example 1Preparation of Diketone Compound E (Scheme VI) 3-Ethylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione
To a 250 ml, three-necked flask equipped with a thermometer, a reflux condenser and mechanical stirrer was charged 3-amino-4-ethylpyrazole oxalate (10 g, 50 mmole), dimethylmalonate (10 ml, 88 mmole), methyl alcohol (80 ml) and sodium methoxide (50 ml, 245 mmole, 25% in methyl alcohol). The batch was heated at reflux for 16 hours then cooled to room temperature. Celite (5 g) and water (60 ml) were added to the batch and agitated for 10 minutes. The batch was filtered to remove the solid residue. The filtrate was pH adjusted to pH˜3 with aqueous HCl (10 ml) to effect precipitation. The precipitate (compound “E”) was filtered and washed with water (40 ml). The wet cake was dried for 18 hours in vacuum oven maintained in the range of oven at 45° C. to 55° C., to give a solid product (84.3%, 7.5 g). C8H9N3O3, Mp: 200-205° C.; NMR in DMSO-d6: 1.05 (t, 3H), 2.23 (q, 2H), 3.26 (bs, 1H), 3.89 (bs, 1H), 7.61 (s, 1H), 11.50(bs, 1H).
Example 2Preparation of Dichloride Compound F (Scheme VI) 5,7-Dichloro-3-Ethylpyrazolo[1,5-a]pyrimidine
Into a 3-neck flask fitted with an inert gas inlet, a reflux condenser and a mechanical stirring apparatus and containing 83 liters of acetonitrile was placed 3-Ethylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (E) prepared as described in Step 1 (11.0 kg, 61.5 mole), N,N-dimethylaniline (8.0 L, 63 mole) and POCl3 (7 kg, 430 mole). With stirring the mixture was brought to reflux and maintained under refluxing conditions for 15 hours. The reaction mixture was sampled periodically to monitor the amount of compound “E” present. After the conversion was complete, the solution was cooled to 15° C. Into the cooled reaction mixture was added water which had been cooled to a temperature of less than 20° C. The product is filtered and washed with 4 aliquots of acetonitrile-water (1:3) which had been cooled to a temperature of 20° C. followed by a wash with 10× water. The wet cake is dried in a vacuum oven maintained at 40° C. for at least 15 hours to yield the compound “F” (86.7%); 1H NMR (CDCl3): 1.32(t, 3H), 2.81 (q, 2H), 6.92 (s, 1H), 8.10 (s, 1H)
mp: 90-95° C.
Example 3Preparation of Compound G (Scheme VI) 5-Chloro-3-Ethyl-N-[(1-oxido-pyridinyl)methyl]pyrazolo-[1,5-a]pyrimidine-5.7(4H,6H)-dion-7-amine
Into a 3-liter, three-necked flask equipped with a thermometer, a reflux condenser and mechanical stirrer was charged an aliquot of the dichloride compound “F” prepared in Step 2 (150 g, 0.69 mole), potassium phosphate tribasic monohydrate (338.0 g, 1.47 mole), the dihydrochloride salt of N-oxide-pyridin-3-yl-methylamine, compound F1a (142.5 g, 0.72 mole), water (1500 ml) and acetonitrile (300 ml). The batch was heated at reflux for 6 hours. At the end of the refluxing period the batch was cooled to room temperature over 2 hours and then held at room temperature for 4 hours. The resulting precipitate was filtered and washed with water (600 ml). The wet cake was returned to the flask with water (1500 ml) and acetonitrile (300 ml), and heated to reflux. Reflux was maintained for 6 hours additional. At the end of the second reflux period the reaction mixture was cooled to room temperature over a 2 hour period and left to stand at room temperature for 4 hours. The resulting precipitate was filtered and washed with water (600 ml). The wet cake was dried in an air draft oven at 50° C. for 18 hours to give the first amine adduct “G” material (179 g, 84.9%). mp: 187-189C; NMR in CDCl3, 1.26(t, 3H), 2.73(q, 2H), 4.60(d, 2H), 5.87(s, 1H), 6.83(bs, 1H), 7.33(t, 1H), 7.70(d, 1H), 7.84(s, 1H), 8.58(d, 1H), 8.64(d, 1H).
Example 4
Preparation of the Compound of Formula II (Scheme VI) 1-[3-Ethyl-7-[(1-oxido-3-pyridinyl)methyl]amino]pyrazolo[1,5-a]pyrimidin-5-yl]-2(s)-piperidinemethanol
Into a three-neck flask fitted with a mechanical stirrer and a reflux condenser were placed the first amine adduct prepared in Step 3, compound “G”, (7 kg, 23 mole), amino-alcohol compound G1a (5.6 kg, 43.3 mole), sodium carbonate (3.5 kg, 33.0 mole), 110 ml of water and 1-methyl-2-pyrrolidinone (NMP) (11 L). The reaction mixture was heated to 150° C. for 4 days. After chromatography indicated that the reaction was complete (90-95% substrate consumed), the reaction mixture was cooled to room temperature and quenched by adding water. The mixture was then extracted with ethyl acetate. The batch was dried by distillation of the water azeotrope under atmospheric pressure and concentrated to about 28 L volume. THF was added and the solution was heated to reflux until all the solids dissolve. Ethyl acetate and trietylamine are added to the hot solution. The batch was cooled to ambient and then agitated with the temperature maintained in the range of from 20° C. to 25° C. for 12 hours. The solids were collected by filtration, washed first with ethyl acetate then water, and dried in the filter under vacuum for 24 hours with the temperature maintained at from 40° C. to 50° C., yielding 4.9 kg, 51.3% of the compound of Formula II.
DSC, 168.6° C.; Specific Rotation (10 mg/ml in MeOH, 20° C.), −117.8 °;
1HNMR (400 MHz, DMSO): 8.31 ppm (1H, s), 8.11-8.13 ppm (1H, td, J=5.7 Hz, J=1.4 Hz), 7.97 ppm (1H, t, J=6.7 Hz), 7.68 ppm (1H, s), 7.41 ppm (1H, s), 7.37-7.43 ppm (1H, dd), 5.55 ppm (1H, s), 4.85 ppm (1H, t, J=5.4 Hz), 4.49-4.59 ppm (3H, m), 4.24-4.28 ppm (1H, broad), 3.27-3.46 ppm (2H, m), 2.76-2.83 ppm (1H, t, J=13.0 Hz), 2.45-2.50 ppm (2H, q, J=7.5 Hz), 1.72-1.79 (1H, m), 1.54-1.68 ppm (6H, m), 1.30-1.34 ppm (1H, m), 1.16 ppm (3H, t, J=7.5 Hz)
Patent Submitted Granted
Process and intermediates for the synthesis of (3-alkyl-5-piperidin-1-yl-3,3a-dihydro-pyrazolo[1,5-a]pyrimidin-7-yl)-amino derivatives and intermediates [US8076479]2008-03-06 GRANT2011-12-13
Process for resolving chiral piperidine alcohol and process for synthesis of pyrazolo[1,5-a] pyrimidine derivatives using same [US7786306]2008-02-28 GRANT2010-08-31
Sequential Administration of Chemotherapeutic Agents for Treatment of Cancer [US2011129456]2011-06-02
TARGETING CDK4 AND CDK6 IN CANCER THERAPY [US2011009353]2011-01-13
Pyrazolopyrimidines as cyclin dependent kinase inhibitors [US2007225270]2007-09-27
PYRAZOLO[1,5-a]PYRIMIDINES [US2007275963]2007-11-29
Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors [US2007281951]2007-12-06
Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors [US2008050384]2008-02-28
Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors [US2007054925]2007-03-08
Entinostat
CAS 209783-80-2
209784-80-5 (HCl)
Bayer Schering Pharma Aktiengesellschaft
Pyridin-3-ylmethyl N-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]carbamate
Entinostat, developed by Syndax Pharmaceuticals, is an oral selective histone deacetylase (HDAC) inhibitor primarily targeting class IHDACs (HDAC1, HDAC2, and HDAC3) . It was later licensed to
Jiangsu Hengrui Medicine Co., Ltd., for development and commercialization in China. In 2024, Entinostat has been approved by the NMPA for use in combination with exemestane to treat advanced breast cancer that is HR-positive and HER2-negative.
KHK and Syndax partner for breast cancer treatment entinostat in Japan and Korea
Japan-based Kyowa Hakko Kirin (KHK) has signed a license agreement with US-based Syndax Pharmaceuticals for the exclusive rights to develop and commercialise entinostat in Japan and Korea.
TOKYO and WALTHAM, Mass., Jan. 7, 2015 /PRNewswire/ — Kyowa Hakko Kirin Co., Ltd., (Headquarters: Chiyoda-ku, Tokyo; president and CEO: Nobuo Hanai, “Kyowa Hakko Kirin”) and Syndax Pharmaceuticals, Inc., (Waltham, Mass.; president and CEO:Arlene M. Morris, “Syndax”) today jointly announced that the companies have entered into a license agreement for the exclusive rights to develop and commercialize entinostat in Japan and Korea. Entinostat is a Class I selective histone deacetylase (HDAC) inhibitor being developed by Syndax in the United States and Europe in combination with hormone therapy for advanced breast cancer and immune therapy combinations in solid tumors.
Entinostat, also known as SNDX-275 and MS-275, is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers.[1]
Entinostat inhibits class I HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM, respectively.[2]
Entinostat (formerly known as MS-275) is a histone deacetylase (HDAC) inhibitor in phase III clincal trials at Syndax in combination with exemestane for the treatment of advanced HR-positive breast cancer.
Entinostat (MS-275) preferentially inhibits HDAC1 (IC50=300nM) over HDAC3 (IC50=8µM) and has no inhibitory activity towards HDAC8 (IC50>100µM). MS-275 induces cyclin-dependent kinase inhibitor 1A (p21/CIP1/WAF1), slowing cell growth, differentiation, and tumor development in vivo. Recent studies suggest that MS-275 may be particularly useful as an antineoplastic agent when combined with other drugs, like adriamycin.
In September 2013, Syndax Pharmaceuticals entered into a licensing, development and commercialization agreement with Eddingpharm in China and other asian countries. In 2013, a Breakthrough Therapy Designation was assigned to the compound for the treatment of locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer when added to exemestane in postmenopausal women whose disease has progressed following non-steroidal aromatase inhibitor therapy.
There is an ongoing phase II trial studying the effect of entinostat on Hodgkin’s lymphoma.[3] It is in other phase II trials for advanced breast cancer (in combination with aromatase inhibitors)[4] and for metastatic lung cancer (in combination with erlotinib).[5] As of September 2013, the Food and Drug Administration is working with the industry to design phase III clinical trials. They seek to evaluate the application of Entinostat for the reduction, or prevention of, treatment resistance to aromatase inhibitors in hormone receptor positive breast cancer.[6] Syndax pharmaceuticals currently holds the rights to Entinostat and recently received $26.6 million in funds to advance treatments of resistant cancers using epigenetic tools.[7]
PHASE 3………..SYNDAX, BREAST CANCER
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Entinostat, developed by Syndax Pharmaceuticals, is an oral selec
tive histone deacetylase (HDAC) inhibitor primarily targeting class I
HDACs (HDAC1, HDAC2, and HDAC3) [7]. It was later licensed to
Jiangsu Hengrui Medicine Co., Ltd., for development and commercial
ization in China. In 2024, Entinostat has been approved by the NMPA for
use in combination with exemestane to treat advanced breast cancer that
is HR-positive and HER2-negative. This approval is specifically for pa
tients whose disease has progressed following prior endocrine therapy
[8]. Entinostat inhibits HDACs, increasing histone acetylation and
reactivating tumor suppressor genes. This mechanism restores sensi
tivity to endocrine therapy and prevents cancer cell proliferation [9].
The therapeutic agent exerts its effects by modulating the tumor
microenvironment through the suppression of immune regulatory cells,
thereby augmenting the immune response. Its clinical efficacy was
confirmed in the E2112 trial (NCT02115282), a global Phase III study.
When used in combination with exemestane, Entinostat demonstrated
the ability to extend PFS in patients with HR-positive, HER2-negative
breast cancer [10]. The median PFS was significantly extended to 6.32
months, contrasting with the 3.72 months observed in the control
cohort. In terms of safety profile, Entinostat demonstrated favorable
tolerability. The frequently encountered adverse events were primarily
neutropenia, fatigue, and nausea. Severe neutropenia occurred in 43 %
of patients but was manageable with supportive care. Liver function
abnormalities were reported but manageable with dose adjustments
[11].
The synthetic route of Entinostat is shown in Scheme 2 [12].
Enti-001 is first treated with trifluoroacetic anhydride to afford
Enti-002. Reaction of Enti-002 with oxalyl chloride yields the acyl
chloride intermediate, which undergoes condensation with Enti-003 to
form Enti-004. Subsequent alkaline hydrolysis of Enti-004 produces
Enti-005. This compound is activated with CDI followed by reaction
with Enti-006 to generate Enti-007. The synthesis concludes with acidic removal of the Boc protecting group from Enti-007, yielding Entinostat
[8] W. Li, Z. Sun, Mechanism of action for HDAC inhibitors-insights from omics
approaches, Int. J. Mol. Sci. 20 (2019) 1616.
[9] N. Bharathy, N.E. Berlow, E. Wang, J. Abraham, T.P. Settelmeyer, J.E. Hooper, M.
N. Svalina, Z. Bajwa, M.W. Goros, B.S. Hernandez, J.E. Wolff, R. Pal, A.M. Davies,
A. Ashok, D. Bushby, M. Mancini, C. Noakes, N.C. Goodwin, P. Ordentlich, J. Keck,
D.S. Hawkins, E.R. Rudzinski, A. Mansoor, T.J. Perkins, C.R. Vakoc, J.E. Michalek,
C. Keller, Preclinical rationale for entinostat in embryonal rhabdomyosarcoma,
Skelet Muscle 9 (2019) 12.
[10] B. Xu, Q. Zhang, X. Hu, Q. Li, T. Sun, W. Li, Q. Ouyang, J. Wang, Z. Tong, M. Yan,
H. Li, X. Zeng, C. Shan, X. Wang, X. Yan, J. Zhang, Y. Zhang, J. Wang, L. Zhang,
Y. Lin, J. Feng, Q. Chen, J. Huang, L. Zhang, L. Yang, Y. Tian, H. Shang, Entinostat,
a class I selective histone deacetylase inhibitor, plus exemestane for Chinese
patients with hormone receptor-positive advanced breast cancer: a multicenter,
randomized, double-blind, placebo-controlled, phase 3 trial, Acta Pharm. Sin. B 13
(2023) 2250–2258.
[11] E.T. Roussos Torres, W.J. Ho, L. Danilova, J.A. Tandurella, J. Leatherman, C. Rafie,
C. Wang, A. Brufsky, P. LoRusso, V. Chung, Y. Yuan, M. Downs, A. O’Connor, S.
M. Shin, A. Hernandez, E.L. Engle, R. Piekarz, H. Streicher, Z. Talebi, M.A. Rudek,
Q. Zhu, R.A. Anders, A. Cimino-Mathews, E.J. Fertig, E.M. Jaffee, V. Stearns, R.
M. Connolly, Entinostat, nivolumab and ipilimumab for women with advanced
HER2-negative breast cancer: a phase Ib trial, Nat Cancer 5 (2024) 866–879.
[12] T. Suzuki, T. Ando, K. Tsuchiya, T. Nakanishi, A. Saito, S. Yamashita, G. Shiraishi,
E. Tanaka, Preparation of Benzamide Derivatives as Anticancer Agents, 1998
JP10152462
SEE SCHEME AT END
Patent
http://www.google.im/patents/WO2010022988A1?cl=en
In EP 0 847 992 A1 (which co-patent is US 6,794,392) benzamide derivatives as medicament for the treatment of malignant tumors, autoimmune diseases, de- rmatological diseases and parasitism are described. In particular, these derivatives are highly effective as anticancer drugs, preferred for the haematological malignancy and solid tumors. The preparation of N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide is described on page 57, Example 48. The compound is neither purified by chromatography nor purified by treatment with charcoal. The final step of the process comprises the re- crystallization from ethanol.
Said compound has a melting point (mp) of 159 – 160 0C.
The IR spectrum shows the following bands: IR(KBr) cm“1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form.
In EP 0 974 576 B1 a method for the production of monoacylated phenylenediamine derivatives is described. The preparation of N-(2- aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl] benzamide is described on pages 12 to 13, Example 6. The final step of the process comprises the purification of the compound via silica gel column chromatography.
Said compound has a melting point (mp) of 159 – 160 0C.
The IR spectrum shows the following bands: IR(KBr) cm‘1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form. In J. Med. Chem. 1999, 42, 3001-3003, the synthesis of new benzamide derivatives and the inhibition of histone deacetylase (HDAC) is described. The process for the production of N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth- oxycarbonylaminomethyl] benzamide is described. The final step of the process comprises the purification of the compound via silica gel column chromatography (ethyl acetate).
Said compound has a melting point (mp) of 159 – 160 0C.
The IR spectrum shows the following bands: IR(KBr) cm‘1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form.
In WO 01/12193 A1 a pharmaceutical formulation comprising N-(2- aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl]benzamide is described.
In WO 01/16106 a formulation comprising N-(2-aminophenyl)-4-[N-(pyridine-3- yl)methoxycarbonylamino-methyl]benzamide, having an increased solubility and an improved oral absorption for benzamide derivatives, and pharmaceutically acceptable salts thereof are described.
In WO 2004/103369 a pharmaceutical composition is described which comprises histone deacetylase inhibitors. That application concerns the combined use of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino- methyl]benzamide together with different cancer active compounds. In fact that application is a later application, which is based on the above mentioned matter and thus concerns the Polymorph A form. Finally, JP 2001-131130 (11-317580) describes a process for the purification of monoacylphenylenediamine derivatives. In Reference Example 2, the process for the production of crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth-oxycarbonylaminomethyl] benzamide is described. Said compound has a melting point (mp) of 159 – 160 0C,
The IR spectrum shows the following bands: IR(KBr) cm“1: 3295, 1648, 1541 , 1508, 1457, 1309, 1183, 742.
The data indicate the Polymorph A form.
Moreover, Working Example 1 describes the purification of crude N-(2- aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethyl] benzamide in aqueous acid medium together with carbon The final crystallization is done under aqueous conditions at 40-500C.
Following the description to that example it can be seen from the Comparative Examples 1 – 3 that the crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth- oxycarbonylaminomethyl] benzamide is not purified by dissolution under reflux conditions in either ethanol, methanol or acetonithle followed by a recrystalliza- tion at 2°C. As a result, these recrystallisations do not yield any pure compound.
In addition a “purification” of crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethyl] benzamide in ethanol under reflux conditions to- gether with carbon is dechbed. After filtering off the carbon the compound is re- crystallized at 2°C. The purification effect of this method is very limited. 1 ,1 % of an impurity remain in the N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethyl] benzamide. As a result, this procedure does not yield any pure compound.
None of the state of the art documents refer to a polymorph B of N-(2- aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl]benzamide and no physicochemical features of said compound are known. Several biological and clinical studies have been done with N-(2-aminophenyl)- 4-[N-(pyridine-3-yl) meth-oxycarbonylaminomethyl] benzamide. For example, Kummar et al., Clin Cancer Res. 13 (18), 2007, pp 5411-5417 describe a phase I trial of N-(2-aminophenyl)-4-[N-(pyridine-3-yl) meth-oxycarbonylaminomethyl] benzamide in refractory solid tumors. The compound was applied orally.
The crude N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]- benzamide of step a) can be produced according to the method described in example 6 of EP 0974 576 B1.
PATENT
http://www.google.co.in/patents/EP0974576A2?cl=en
Example 6Synthesis of N-(2-aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide (an example in which after activation with N,N’-carbonyldiimidazole, an acid was added to carry out reaction)
| Retention Time/min. | Area % | |
| Benzoylimidazole as Active Intermediate | 4.3 | 0.00 |
| Monoacylated Phenylenediamine | 4.7 | 98.91 |
| Diacylated Phenylenediamine | 11.7 | 1.09 |
Analysis data of the product
mp. 159-160°C
1H NMR (270MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J=5.9Hz), 4.86 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J=7.3Hz), 6.78 (1H, d, J=7Hz), 6.97 (1H, t, J=7Hz), 7.17 (1H, d, J=8Hz), 7.3-7.5 (3H, m), 7.78 (1H, d, J=8Hz), 7.93 (2H, d, J=8Hz), 8.53 (1H, d, J=3.7Hz), 8.59 (1H, s), 9.61 (1H, s).
IR (KBr) cm-1: 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742
PATENT
WO 2009076206
http://www.google.com/patents/WO2009076206A1?cl=en
Suzuki et al (Suzuki et al Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives, J Med Chem 1999, 42, (15), 3001-3) discloses benzamide derivatives having histone deacetylase inhibitory activity and methods of making benzamide derivatives having histone deacetylase inhibitory activity. Suzuki et al is hereby incorporated herein by reference in its entirety.
[18] An example of the synthesis method of Suzuki et al to produce MS-275 via a three- step procedure in 50.96% overall yield is outlined in Scheme 3 below.
Scheme 3: Previous Procedure for Synthesis of MS-275 en rt, 4h
(used without purification)
[Overall yield: 0.91 x 0.56 x 100 = 50.96%;
MS-275 [19] In addition to the modest overall yield, the procedure of Suzuki et al has other disadvantages, such as a tedious method for the preparation of an acid chloride using oxalyl chloride and requiring the use of column chromatography for purification.
The synthesis of MS-275 is shown below in Scheme 4 as an example of Applicants invention of a two-step procedure: [37] Scheme 4: Preparation of MS-275
Scheme 4: New Synthesis of MS-275 (4)
Condensation of 3-(hydroxymethyl)pyridine (7) and 4-(aminomethyl)benzoic in the presence of CDI gave 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic Acid (8) in 91.0% yield. In the previous method of Suzuki et ah, the carboxylic acid derivative 8 was first converted into acyl chloride hydrochloride by treatment of oxalyl chloride in toluene and then reacted with imidazole to form the acylimidazole intermediate. (Suzuki et al., Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 1999, 42, (15), 3001-3.). However, Applicants synthesized the imidazolide of intermediate 8 by treatment with CDI at about 55-60 0C in THF. The imidazolide was cooled to ambient and further reacted in situ with 1,2-phenylenediamine in the presence of TFA to afford MS-275
(4).
Experimental Section
[62] iV-(2-Aminophenyl)-4-[iV-(pyridin-3-ylmethoxycarbonyl) aminomethyl] benzamide (4, MS-275).
[63] To a suspension of 4-[N-(Pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic
Acid (5.0 g, 0.017 mol) in THF (100 mL) was added CDI (3.12 g, 0.019 mol), and the mixture stirred for 3 h at 60 0C. After formation of acylimidazole the clear solution was cooled to room temperature (rt). To this was added 1,2-phenylenediamine (15.11 g, 0.14 mmol) and trifluoroacetic acid (1.2 mL, 0.015 mol) and then stirred for 16 h. The reaction mixture was evaporated to remove THF and crude product was stirred in a mixture of hexane and water (2:5, v/v) for 1 h and filtered and dried. The residue was stirred in dichloromethane twice to afford pure MS-275 (4) as off white powder 5.25 g, 80% yield:
mp 159-160 * C; IR (KBr) 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742 cm“1.
1H NMR (DMSO-J6) δ 4.28 (d, 2H, J = 5.9 Hz), 4.86 (s, 2H), 5.10 (s, 2H), 6.60 (t, IH, J = 7.3 Hz), 6.78 (d, IH, J = 7 Hz), 6.97 (t, IH, J= 7 Hz), 7.17 (d, IH, J= 8 Hz), 7.3-7.5(m, 3H), 7.78 (d, IH, J= 8 Hz), 7.93 (d, 2H, J = 8 Hz), 8.53 (d, IH, J = 3.7 Hz), 8.59 (s, IH), 9.61 (s, IH);
HRMS: calcd 376.1560 (C2iH2oN4θ3), found 376.1558. These spectral and analytical data are as previously reported in J Med Chem 1999, 42, (15), 3001-3.
[64] 4-[7V-(Pyridin-3-ylmethoxycarbonyI)aminomethyl] benzoic Acid (8) may be prepared as follows. To a suspension of l, l’-carbonyldiimidazole (CDI, 25.6 g, 158 mmol) in THF (120 mL) was added 3-pyridinemethanol (7, 17.3 g, 158 mmol) in THF (50 mL) at 10 0C, and the mixture stirred for 1 h at rt. The resulting solution was added to a suspension of 4-(aminomethyl)benzoic acid (22.6 g, 158 mmol), DBU (24.3 g, 158 mmol), and triethylamine (22.2 mL, 158 mmol) in THF (250 mL). After stirring for 5 h at rt, the mixture was evaporated to remove THF and then dissolved in water (300 mL). The solution was acidified with HCl (pH 5) to precipitate a white solid which was collected by filtration, washed with water (300 mL) and methanol (50 mL), respectively, and dried to yield pure 8 (41.1 g, 91% yield):
mp 207-208 0 C;
IR (KBr) 3043, 1718, 1568, 1434, 1266, 1 108, 1037, 984, 756 cm4; 1H NMR (DMSO-^6) δ 4.28 (d, 2H, J= 5.9 Hz), 5.10 (s, 2H), 7.3-7.5 (m, 3H), 7.7-8.1 (m, 4H), 8.5-8.7 (m, 2H). These spectral and analytical data are as previously reported in Suzuki et al, J Med Chem 1999, 42, (15), 3001-3.
PAPER
Volume 18, Issue 11, 1 June 2010, Pages 3925–3933
http://www.sciencedirect.com/science/article/pii/S0968089610003378
PAPER
see
Bioorg Med Chem 2008, 16(6): 3352
http://www.sciencedirect.com/science/article/pii/S0968089607010577
PAPER
see
Bioorganic and Medicinal Chemistry Letters, 2004 , vol. 14, 1 pg. 283 – 287
http://www.sciencedirect.com/science/article/pii/S0960894X03010539
PAPER
J Med Chem 1999, 42(15): 3001
http://pubs.acs.org/doi/abs/10.1021/jm980565u
N-(2-Aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide (1, MS-275). To a solution of imidazole (0.63 g, 9.2 mmol) in THF (20 mL) was added 3 (1 g, 2.9 mmol), and the mixture stirred for 1 h at room temperature. After imidazole hydrochloride was removed by filtration, 1,2-phenylenediamine (2.52 g, 23.2 mmol) and trifluoroacetic acid (0.2 mL, 2.6 mmol) were added to the filtrate and stirred for 15 h. The reaction mixture was evaporated to remove THF and partitioned between ethyl acetate (500 mL) and water (400 mL). The organic layer was washed with water and dried and then purified by silica gel column chromatography (ethyl acetate) to give 1 (0.62 g, 56% yield):
mp 159−160 °C;
1H NMR (DMSO-d6) δ 4.28 (d, 2H, J = 5.9 Hz), 4.86 (s, 2H), 5.10 (s, 2H), 6.60 (t, 1H, J = 7.3 Hz), 6.78 (d, 1H, J = 7 Hz), 6.97 (t, 1H, J = 7 Hz), 7.17 (d, 1H, J = 8 Hz), 7.3−7.5(m, 3H), 7.78 (d, 1H, J = 8 Hz), 7.93 (d, 2H, J = 8 Hz), 8.53 (d, 1H, J = 3.7 Hz), 8.59 (s, 1H), 9.61 (s, 1H);
IR (KBr) 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742 cm-1.
Anal. (C21H20N4O3) C, H, N.
………………………………………………………………………..
see
Bulletin of the Korean Chemical Society, 2014 , vol. 35, 1 pg. 129 – 134
http://koreascience.or.kr/article/ArticleFullRecord.jsp?cn=JCGMCS_2014_v35n1_129
PAPER
see
ChemMedChem, 2013 , vol. 8, 5 pg. 800 – 811
PAPER
see
ACS Medicinal Chemistry Letters, 2013 , vol. 4, 10 pg. 994 – 999
http://pubs.acs.org/doi/full/10.1021/ml400289e
| Cited Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| EP0847992B1 * | Sep 30, 1997 | Jun 23, 2004 | Schering Aktiengesellschaft | Benzamide derivatives, useful as cell differentiation inducers |
| US7244751 * | Feb 2, 2004 | Jul 17, 2007 | Shenzhen Chipscreen Biosciences Ltd. | N-(2-amino-5-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide or other derivatives for treating cancer and psoriasis |
| Reference | ||
|---|---|---|
| 1 | * | MAI A: ‘Histone deacetylation in epigenetics: an attractive target for anticancer therapy‘ MED RES REV. vol. 25, no. 3, May 2005, pages 261 – 309 |
| 2 | * | SUZUKI T ET AL.: ‘Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives‘ J MED CHEM. vol. 42, no. 15, 29 July 1999, pages 3001 – 3003 |
| Names | |
|---|---|
| Preferred IUPAC name(Pyridin-3-yl)methyl ({4-[(2-aminophenyl)carbamoyl]phenyl}methyl)carbamate | |
| Other namesSNDX-275; MS-275 | |
| Identifiers | |
| CAS Number | 209783-80-2 |
| 3D model (JSmol) | Interactive image |
| ChEBI | CHEBI:132082 |
| ChEMBL | ChEMBL27759 |
| ChemSpider | 4111 |
| ECHA InfoCard | 100.158.999 |
| IUPHAR/BPS | 7007 |
| KEGG | D09338 |
| PubChem CID | 4261 |
| UNII | 1ZNY4FKK9H |
| CompTox Dashboard (EPA) | DTXSID0041068 |
InChI | |
| SMILES | |
| Properties | |
| Chemical formula | C21H20N4O3 |
| Molar mass | 376.4085 g/mol |
| Pharmacology | |
| ATC code | L01XH05 (WHO) |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).verify (what is ?)Infobox references | |
/////////////////approvals 2024, china 2024, Entinostat, SNDX 275, MS 275, Syndax, BAY 86-5274, BAY86-5274
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……
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
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 |
Abaloparatide
WALTHAM, Mass., Dec. 21, 2014 (GLOBE NEWSWIRE) — Radius Health, Inc. today announced positive top-line 18-month fracture results from the Company’s Phase 3 clinical trial (ACTIVE) evaluating the investigational drug abaloparatide-SC for potential use in the reduction of fractures in postmenopausal osteoporosis.
https://in.finance.yahoo.com/news/radius-announces-positive-phase-3-042531179.html
Abaloparatide
BA058
BIM-44058
UNII-AVK0I6HY2U
BA058; BIM-44058; CAS 247062-33-5
MW 3960.5896, MF C174 H300 N56 O49
NAME………C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-
CLINICAL……….https://clinicaltrials.gov/search/intervention=Abaloparatide%20OR%20BA058%20OR%20BIM-44058
BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.
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PATENT
http://www.google.com/patents/EP2206725A1?cl=en
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SEE……http://www.google.com.ar/patents/US8148333?cl=en
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SEE…………http://www.google.im/patents/US20090227498?cl=pt
| EP5026436A | Title not available | |||
| US3773919 | Oct 8, 1970 | Nov 20, 1973 | Du Pont | Polylactide-drug mixtures |
| US4767628 | Jun 29, 1987 | Aug 30, 1988 | Imperial Chemical Industries Plc | Polylactone and acid stable polypeptide |
| WO1994001460A1 * | Jul 13, 1993 | Jan 20, 1994 | Syntex Inc | Analogs of pth and pthrp, their synthesis and use for the treatment of osteoporosis |
| WO1994015587A2 | Jan 5, 1994 | Jul 21, 1994 | Steven A Jackson | Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides |
| WO1997002834A1 * | Jul 3, 1996 | Jan 30, 1997 | Biomeasure Inc | Analogs of parathyroid hormone |
| WO1997002834A1 * | 3 Jul 1996 | 30 Jan 1997 | Biomeasure Inc | Analogs of parathyroid hormone |
| WO2008063279A2 * | 3 Oct 2007 | 29 May 2008 | Radius Health Inc | A stable composition comprising a bone anabolic protein, namely a pthrp analogue, and uses thereof |
| US5695955 * | 23 May 1995 | 9 Dec 1997 | Syntex (U.S.A.) Inc. | Gene expressing a nucleotide sequence encoding a polypeptide for treating bone disorder |
| US20030166836 * | 6 Nov 2002 | 4 Sep 2003 | Societe De Conseils De Recherches Et D’application Scientefiques, S.A.S., A France Corporation | Analogs of parathyroid hormone |
| US20050282749 * | 14 Jan 2005 | 22 Dec 2005 | Henriksen Dennis B | Glucagon-like peptide-1 (GLP-1); immunotherapy; for treatment of obesity |
Fostemsavir
GSK3684934
CAS 864953-29-7
[3-[2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate
Fostemsavir (GSK3684934/BMS-663068) is an experimental HIV entry inhibitor and a prodrug of temsavir (BMS-626529). It is under development by [ViiV Healthcare / GlaxoSmithKline]] for use in the treatment of HIV infection. By blocking the gp120 receptor of the virus, it prevents initial viral attachment to the host CD4+ T cell and entry into the host immune cell; its method of action is a first for HIV drugs.[1] Because it targets a different step of the viral lifecycle, it offers promise for individuals with virus that has become highly resistant to other HIV drugs.[2] Since gp120 is a highly conserved area of the virus, the drug is unlikely to promote resistance to itself via generation of CD4-independent virus.[3]
Example 6Preparation of Compound I from Compound D′ (Example 5)
N-Benzoylpiperazine HCl, Compound Db, (11.73 g, 51.74 mmol) was added to a mixture of Compound D′ (14.83 g, 47.03 mmol) (prepared in Example 5) in dry THF (265 mL) and dry DMF (29.5 mL). NaOt-Bu, 30% w/w (52.3 mL, 147 mmol) was added dropwise (30 min.) keeping the temperature at 17-21° C. The resulting yellow slurry was stirred at 17-20° for 1 h more, then cooled to about 5° C. The mixture was slowly poured into cold water (90 mL) and the flask rinsed with additional water (10 mL). The pH of the resulting yellow solution was adjusted to 6-7 with slow addition (˜20 min., 5-12° C.) of 1 N HCl (105 mL). The resulting slurry was warmed and stirred at room temperature for 1.5 h. The slurry was filtered and the cake washed with water (2×60 mL) then dried in vacuo at 65-70° C. for 5 h giving 18.4 g Compound I as a white solid (82.6%), HPLC AP 99.4. 1H NMR (400 MHz, d6-DMSO): δ 2.48 (s, 3H), 3.43 (b, 4H), 3.67 (b, 4H), 3.99 (s, 3H), 7.45 (s, 5H), 7.88 (s, 1H), 8.24 (s, 1H), 9.22 (s, 1H), 12.39 (s, 1H). 13C NMR (100 MHz, d6-DMSO): 13.85, 40.65, 45.22, 56.85, 114.19, 121.02, 122.78, 123.65, 127.06, 128.42, 129.61, 129.70, 135.51, 138.59, 142.18, 149.23, 161.38, 166.25, 169.30, 185.51.
If necessary, the product could be further purified by recrystallization from acetic acid-water-ethanol, ethanol-water, or acetone-water. For example: A mixture of Compound I (25.0 g), glacial acetic acid (260 mL) and DI water (13.8 mL) was heated to 80° C. and held with stirring (overhead) until a solution was obtained (40 min.). The batch was cooled to 70° C. and seeded (0.5 g). With slow agitation (100 rpm), EtOH (300 mL) was added slowly (1 h), keeping the temperature at 70° C. The resulting slurry was kept at 70° C. for 1 h more with very slow stirring. The slurry was cooled to 20° C. over 2 hours and held at 20° C. for over 4 hours. The slurry was filtered, the wet cake washed with EtOH (125 mL), and the solid dried in vacuo at 70° C. (≧16 h), giving 22.6 g Compound I as a white solid (88.4%).
The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel–Crafts acylation, Pictet–Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C–H bond, enabling a highly regioselective copper-mediated Ullmann–Goldberg–Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate
Attachment inhibitor BMS-663068 is currently in clinical development for the treatment of HIV infection. Key steps in the synthesis depicted are (1) a radical-mediated redox-aromatization to generate the 6-azaindole (B → C) and (2) the regioselective bromination of an N-oxide using PyBroP (D → E).
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http://www.google.com/patents/US20050209246
Preparation of Compound IVc
Procedure: To a solution of the acid 6-81 (3.01 g, 10 mmol) and benzoylpiperazine hydrochloride (3.39 g, 15 mmol) in DMF (50 mL) was added triethylamine (10.1 g, 100 mmol, 10 eq.), followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 5.75 g, 30 mmol) under N2 and the mixture stirred at room temperature for 22 h after sonication and at 40° C. for 2 h. The mixture was concentrated in vacuo to remove DMF and TEA, and to the residual solution was added water (200 mL) under stirring and sonication. The precipitates formed were collected, washed with water and dried in vacuo to obtain 2.8 g (5.9 mmol, Y. 59%) of the title compound IVc as off-white solid. The filtrate was extracted with CH2Cl2 (x2). The CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated to gum which was triturated with Et2O to obtain a solid. This solid was suspended and triturated with MeOH to obtain 400 mg of the title compound IVc as off-white solid. Total yield: 3.2 g (6.8 mmol, Y. 68%): MS m/z 474 (MH); HRMS (ESI) m/z calcd for C24H24N7O4 (M+H) 474.1890, found 474.1884 (Δ-1.2 ppm); 1H NMR (DMSO-d6) δ ppm 2.50 (3H, s, overlapped with DMSO peaks), 3.43 (4H, br, CH2N), 3.68 (4H, br, CH2N), 3.99 (3H, s, CH3O), 7.46 (5H, br. s, Ar—Hs), 7.88 (1H, s, indole-H-5), 8.25 (1H, s, indole-H-2), 9.25 (1H, s, triazole-H-5), 12.40 (1H, s, NH); 13C-NMR (DMSO-d6) δ ppm 13.78 ,40.58, 45.11, 56.78, 114.11, 120.95, 122.71, 123.60, 126.98, 128.34, 129.6, 135.43, 138.52, 142.10, 149.15, 161.29, 166.17, 169.22, 185.42; UV (MeOH) λ max 233.6 nm (ε 3.43×104), 314.9 nm (ε 1.73×104); Anal: Calc for C24H24N7O4.1/5H2O; C, 60.42; H, 4.94; N, 20.55, Found; C 60.42, H 5.03, N 20.65; KF (H2O) 0.75%.
This reaction can also be performed by use of HATU and DMAP to provide more consistent yield of the title compound: To a suspension of the acid 6-81 (15.6 mmol) and HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophos phonate] (8.90 g, 23.4 mmol; 1.5 eq.) in DMF (60 mL) and CH2Cl2 (60 mL) was added a mixture of DMAP (5.72 g, 46.8 mmol, 3 eq.) and benzoylpiperazine hydrochloride (5.30 g, 23.4 mmol; 1.5 eq.) in DMF (60 mL) at room temperature and the mixture was stirred under nitrogen atmosphere for 4 hrs. The mixture was concentrated in vacuo to remove CH2Cl2 and most of DMF, and to the residual solution was added water under stirring and sonication. The precipitates formed were collected, washed with water and dried in vacuo to obtain 5.38 g (11.4 mmol, Y. 72.8%) of the title compound IVc as off-white solid: HPLC >95% (AP, uv at 254 nm)
EXAMPLE 5Preparation of Ica, (Disodium Salt)
General Procedure: A suspension of IVc (0.24 g, 0.5 mmol) in anhydrous THF (4 mL) under nitrogen atmosphere was treated with sodium hydride (60% oil dispersion, 0.08 g, 2.0 mmol), and stirred until gas evolution ceased (approximately 5 minutes). The reaction mixture was treated with iodine (0.13 g, 0.5 mmol) and stirred for 2-3 minutes followed by addition of di-tert-butyl chloromethyl phosphate (1.6 g, 6.0 mmol, crude). A stream of nitrogen was allowed to pass over the reaction to facilitate the removal of much or all of the THF. The reaction mixture was stirred overnight. HPLC analysis of crude indicated starting IVc (ca. 56%) and desired adduct (ca. 32%).
Several crude reaction mixtures (a total of 6.7 mmol based on starting material IVc) were re-dissolved in dichloromethane, combined, concentrated in vacuo to remove any remaining THF. The residue was suspended in dichloromethane and TFA (1:1, approximately 40 mL total volume). The mixture was stirred for 1.5-2 hours and then solvent was removed in vacuo. The residue was suspended in dichloromethane and extracted into water (approximately 60 mL) made weakly basic with solid or aqueous sodium bicarbonate. The aqueous layer was reduced in volume by rotary evaporator if required and the solution was loaded onto a C-18 reverse phase column (approximately 80 g of C-18, YMC ODS-Aq, 50 micron) and eluted with water, followed by water containing 2.5% acetonitrile. Fractions containing pure product were pooled and organic solvent was removed by rotary evaporator. Purified product was recovered after lyophilization to give 1.00 g (1.30 mmol, 19% over 2 steps) of the title compound Ica (disodium salt) as an off-white powder: HPLC purity>99% AP at 254 nm (gradient 0-100% B/A; A 10% CH3CN-90% H2O-0.1% TFA, B 90% CH3CN-10% H2O-0.1 % TFA, gradient time 4 min, column YMC ODS-Aq 4.6×50 mm 3 micron); MS-ESI— m/z 482 (M−H minus 2Na)−; HRMS (ESI) m/z calcd for C25H27N7O8P (M+H minus 2Na)+584.1659, found 584.1651 (Δ-1.3 ppm); 1H NMR (D2O, 500 MHz) δ ppm 2.53, 2.54 (3H, 2s), 3.56 (2H, s, CH2N), 3.72 (2H, br.s, CH2N), 3.78, 3.83 (2H, 2br.s, CH2N), 3.94, 3.96 (2H, 2br.s, CH2N), 4.14 (3H, s, CH3O), 5.38, 5.40 (2H, 2d, J=11 Hz), 7.45-7.59 (5H, m, Ar—Hs), 8.07, 8.09 (1H, 2s, indole-H-5), 8.64, 8.67 (1H, 2s, indole-H-2), 8.87, 8.89 (1H, 2s, triazole-H-5); 13C NMR (125.7 MHz, D2O) δ ppm 15.43 (N-Me), 44.03, 44.47, 44.66, 45.05, 48.20, 48.82, 49.60, 50.23, 59.78 (OMe), 75.81 (NCH2O), 115.6, 126.0, 127.2, 129.6, 131.0, 131.7, 132.1, 133.5, 136.8, 147.6, 150.1, 154.2, 164.8, 170.4, 175.8, 189.2; UV (H2O) λmax 220 nm (ε 3.91×104), 249 nm (ε 2.00×104), 303 nm (ε 1.60×104); Anal: Calc for C25H24N7O8PNa2. 8H2O. 0.2NaHCO3; C, 38.39; H, 5.14; N, 12.44, P, 3.93, Na, 6.42 Found; C, 38.16; H, 4.81; N, 12.43, P, 3.72, Na, 6.05; KF (H2O) 17.3%. A less pure fractions were collected to obtain 0.22 g (0.29 mmol, Y. 4%) of the title compound Ica (disodium salt): HPLC purity>95% (AP at 254 nm).
EXAMPLE 7Preparation of Crystalline Ic (Free Acid Mono-Hydrate)
To a mixture of IVc (600 mg, 1.27 mmol) in anhydrous THF (10 ml) in an oven-dried round bottle flask under nitrogen at r.t. was added NaH (153 mg, 6.38 mmol, dry powder, 95%), and the white suspension stirred until no gas evolution was observed. The mixture was then added I2 (375 mg, 1.48 mmol), and stirred at r.t. for 3 h. To the reaction mixture was added NaH (153 mg, 6.38 mmol, dry powder, 95%), and the mixture stirred for about 5 to 10 min. The crude chloromethyl di-tert-butylphosphate (2.0 g, about 1.6 ml, 7.79 mmol) was added to the mixture, which was then stirred at r.t. for 15 h. LCMS analysis of the reaction showed a >97% conversion of the starting material. After evaporation of the volatiles, the residue was added CH2Cl2 (10 ml), cooled in an ice-water bath, slowly added TFA (10 ml) and stirred at r.t. for 3 h. The reaction mixture was then evaporated, and the residue partitioned between CH2Cl2 (50 ml) and H2O (50 ml). The CH2Cl2 layer was poured into the reaction flask that contained some undissolved brownish solid, and this mixture was extracted with a dilute aqueous NaHCO3 solution (50 ml). The aqueous mixture was purified by reverse phase preparative HPLC (solvent A: 10% MeOH-90% H2O-0.1% TFA; solvent B: 90% MeOH-10% H2O-0.1% TFA; start % B=0, final % B=100; gradient time=6 min; flow rate=45 ml/min; column: phenomenex-Luna 30×50 mm, S5; fraction collected: 3.65 to 4.05 min). The fractions collected were evaporated to dryness, and the residue dried under high vacuum to obtain the acid Ic as a pale yellow solid (356.6 mg); 1H NMR: (500 MHz, CD3OD) δ 9.05 (s, 1H), 8.46 (s, 1H), 8.04 (s, 1H), 7.47 (b s, 5H), 5.93 (d, J=12, 2H), 4.10 (s, 3H), 4.00-3.40 (b s, 8H), 2.53 (s, 3H); 19F NMR analysis showed that the material contained residual TFA, (the percentage was not quantified); Analytical HPLC method: Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 mL/min, Column: Xterra MS C18 7u 3.0×50 mm, LC/MS: (ES+) m/z (M+H)+=584, HPLC Rt=0.983.
172.2 mg of the purified acid Ic was dissolved in 1 ml of H2O and then about 0.3 ml of absolute EtOH (200 proof) was added. The mixture was left standing in a refrigerator (temperature about 3° C.) overnight, after which time, crystalline material was observed. The mixture was then warmed to ambient temperature, diluted with H2O to a volumn of 3 mL, and then 20 mL of MeCN was added slowly. Following the completion of addition, the mixture was stirred at r.t. for 2 h and then filtered. The solid collected (90 mg) was dried in vacuo, and then under high vacuum. This material was shown by powder x-ray studies to be crystalline; Elemental Analysis calculated for C25H26N7O8P.H2O: C 49.92; H 4.69; N 16.30; observed: C 49.66; H 4.62; N 15.99; mp=205° C. (measured by differential scanning calorimetry). The 1H NMR pattern for crystalline material was compared with that from the purified acid and both were consistent with the structure.
EXAMPLE 10Preparation of Icb (mono tromethamine salt): [3-[(4-benzoylpiperazin-1-yl)(oxo)acetyl]-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2, 3-c]pyridin-1-yl]methyl dihydrogen phosphate, 2-amino-2-(hydroxymethyl)propane-1,3-diol salt (1:1). The sequence of reactions is described in Scheme for Example 10.
Scheme for Example 10
Preparation of di-tert-butyl chloromethyl phosphate
A mixture of tetrabutylammonium di-tert-butyl phosphate (57 g, 0.126 mol, Digital Specialty Chemicals) and chloroiodomethane (221 g, 1.26 mol) was stirred at room temperature for four hours before the volatiles were removed under vacuum. 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate in vacuo and removal of remaining volatiles using a vacuum pump provided di-tert-butyl chloromethyl phosphate as a light brown or yellow oil, which was utilized in the next step without further purification.
Preparation of IIc: (3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl di-tert-butyl phosphate
NaH (2.6 g, 10.3 mmol, 95% in oil, Seq.) was added slowly into a suspension of IVc (10.0 g, 21.1 mmol) in dry THF (100 ml) and the mixture was allowed to stir for 0.5 hour at room temperature. A solution of iodine (5.27 g, 20.8 mmol) dissolved in dry THF (10 ml) was added slowly into the stirring solution at a rate which prevented foaming or a violent reaction. The resultant mixture was stirred for an additional 3 hours before a second 2.6 g portion of NaH was introduced. After 15 minutes at ambient temperature di-tert-butyl chloromethyl phosphate, the entire batch of di-tert-butyl chloromethyl phosphate, obtained from step one, was added. After stirring for 16 hours, the reaction mixture was poured into iced NH4OAc (30%) (120 ml), followed by extraction with EtOAc (3×300 ml). The combined organic extracts were washed with water (100 ml) and then brine (100 ml), dried over Na2SO4, and concentrated under vacuum to afford a residue, which was purified by silica gel chromatography (elution with EtOAc/Et3N (50/1) and then EtOAc/MeOH (100/1)) to give 8.0 g (˜75% AP, ˜41% yield) of diester IIc as a light yellow solid.
1H NMR (500 MHz, CD3OD) δ8.82 (s, 1H), 8.41 (s, 1H), 8.04 (s, 1H), 7.47 (b, 5H), 6.00 (d, 2H, J=14.5 Hz), 4.10 (s, 3H), 4.00-3.40 (b, 8H), 2.49 (s, 3H), 1.28 (s, 18H); 13C NMR (125 MHz, CD3OD) δ18.6, 176.4, 172.9, 168.0, 162.6, 152.6, 147.5, 144.0, 136.5, 131.5, 130.8, 129.9, 129.1, 128.3, 126.1, 124.0, 116.2, 85.8, 75.4, 61.6, 57.7, 30.1, 22.2, 13.7; HRMS m/z: (M+H)+ calcd for C33H43N7O8P 696.29, found 696.34.
Preparation of Icb (mono L tromethamine salt): [3-[(4-benzoylpiperazin-1-yl)(oxo)acetyl]-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate, 2-amino-2-(hydroxymethyl)propane-1,3-diol salt (1:1)
500 mg (˜p75 AP, 0.54 mmol) of diester IIc was dissolved in a mixture of water (2.5 ml) and acetone (2.5 ml). The resulting mixture was stirred at 40° C. for 16 hours to complete the solvolysis. To this reaction mixture was added 3.0M aqueous TRIS (mono tromethamine) solution to adjust pH to 3.32. Acetone (30 ml) was slowly added to the reaction mixture in 1 hour.* After complete addition of acetone, the solution was stirred overnight to complete the crystallization of Icb. The solid was collected by filtration and rinsed with 20:1 acetone-water (2×5 mL). The white crystalline solid was dried under house vacuum under nitrogen atomosphere at 50° C. for 24 h to afford 290 mg of Icb (>98.5 AP).
*After adding about 15 and 20 ml of acetone, the reaction mixture was seeded with crystalline Icb.
Icb obtained in the above operation: 1H NMR (500 MHz, CD3OD) δ8.83 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H) 7.49 (b, 5H), 5.469 (d, 2H, J=13 Hz), 4.11 (s, 3H), 4.00-3.40 (m, 8H), 3.66 (s, 6H), 2.50 (s, 3H); 13C NMR (125 MHz, CD3OD) δ185.6, 171.9, 167.4, 161.4, 151.7, 146.9, 143.8, 135.4, 130.3, 129.7, 128.8, 127.2, 124.9, 122.6, 114.3, 73.5, 61.8, 59.9, 56,5, 46.0, 41.7, 12.6. HRMS m/z: (M-trisamine+H)+ calcd for C25H27N7O8P 584.1659, found 584.1664. Anal. Calcd. C, 49.43; H, 5.29; N, 15.90; P, 4.39; found: C, 49.18; H, 5.38; N, 15.59; P, 4.26. Melting Point 203° C.
Obtained via other process (hydrolysis with TFA in methylene chloride), salt Icb is ˜1 molar mono tromethamine salt with 0.47% of water, 0.1% of acetone and 0.05% of methanol. 1H NMR (500 MHz, d6-DMSO, 30° C.) δ8.77 (s, 1H), 8.48 (s, 1H), 8.00 (s, 1H) 7.44 (b, 5H), 5.42 (d, 2H, J=15 Hz), 4.02 (s, 3H), 3.70-3.30 (m, 8H), 3.41 (s, 6H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3, 30° C.) δ184.8, 169.0, 165.8, 160.3, 150.4, 146.2, 143.2, 135.4, 129.4, 128.9, 128.2, 127.7, 126.9, 123.2, 122.2, 112.9, 72.3, 60.7, 59.0, 56.7, 13.4. MS m/z: (M-trisamine+H)+ calcd for C25H27N7O8P 584.2, found 584.0. Anal. Calcd. C, 49.11; H, 5.37; N, 15.76; P, 4.32; found: C, 48.88; H, 5.28; N, 15.71; P, 4.16. M.P. 201-205° C.
EXAMPLE 13Alternate preparation of Icb (Pro-drug of IVc)
To a 10 L reactor equipped with an overhead stirrer, thermocouple, distillation apparatus, and nitrogen inlet was charged IVc (200.00 g, 422.39 mmol), Cs2CO3 (344.06 g, 1.06 mol), KI (140.24 g, 844.81 mmol) and NMP (1.00 L, 10.38 mol). The reaction was stirred at room temperature resulting in a light brown heterogeneous suspension. Di-tert-butyl chloromethyl phosphate (273.16 g, 1.06 mol) was added via addition funnel and the reaction mixture was heated to 30° C. for 16-24 hours with stirring after which time the reaction was cooled to 5° C. To the reaction was added DCM (1.5 L) then the reaction was slowly quenched with water (3.5 L) maintaining the reaction temperature under 20° C. resulting in a biphasic mixture. The product rich bottom layer was separated, washed with water (3.5 L×3), then transferred back to the reactor. The solution was concentrated under vacuum to a volume of 1 L keeping the temperature below 25° C. IPA was added (2 L) then the reaction was concentrated under vacuum to a volume of 2 L keeping the temperature below 25° C. The reaction was then seeded with IIc (0.200 g), stirred overnight at room temperature resulting in a slurry. The slurry was filtered and the wet cake was washed with MTBE (1 L), dried in a vacuum oven at 50° C. overnight resulting in a yellow/white powder (207.1 g, 70%). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.42 (s, 5H), 5.95 (d, J=14.2 Hz, 2H), 4.06 (s, 3H), 3.97-3.36 (m, 8H), 2.50 (s, 3H), 1.27 (s, 18H); 3C NMR (100 MHz, CDCl3) δ 184.64, 170.65, 165.91, 161.60, 150.82, 145.38, 141.89, 134.96, 130.20, 129.59, 128.68, 127.58, 127.10, 124.77, 122.64, 115.22, 83.90, 83.83, 73.69, 73.63, 56.95, 46.04, 41.66, 29.61, 29.56, 13.90; ES+ MS m/z (rel. intensity) 696 (MH+,10), 640 (MH+-isobutylene, 30), 584 (MH+-2 isobutylene, 100).
To a 10 L 4 neck reactor equipped with a thermocouple, overhead stirrer, condenser and nitrogen inlet was added IIc (200.24 g, 287.82 mmol), acetone (800.00 ml, 10.88 mol) and water (800.00 ml, 44.41 mol). The reaction was heated to 40° C. and stirred for 18-24 hours. The reaction was cooled to 20° C. then tromethamine (33.62 g, 277.54 mmol) was added. The reaction was heated to 40° C. then stirred for an additional hour until all solids were dissolved. The reaction was cooled to 20° C. then filtered through a 10 micron cuno filter into a 10 L 4 neck reactor equipped with a thermocouple, overhead stirrer, and nitrogen inlet. Acetone (3 L) was added rapidly, followed by seeding with Icb (0.500 g), then additional acetone (3 L) was added. The reaction was stirred at room temperature overnight resulting in a slurry then filtered. The wet cake was washed with acetone (800 ml) then dried in a vacuum oven at 50° C. overnight resulting in a fluffy white powder (165.91 g, 82%).
Supplementary Information:
Isolation of the Free-Acid Intermediate IC:
In a 250 mL 3 neck reactor equipped with a thermocouple, overhead stirrer, condenser and nitrogen inlet was added IIc (10.0 g, 14.37 mmol), acetone (40.00 ml, 544.15 mmol) and water (40.00 ml, 2.22 mol). The reaction was heated to 40° C. and stirred for 14-24 hours. The reaction was cooled to 20° C. then stirred for three hours, resulting in a slurry. The slurry was filtered, then the wet cake washed with acetone (40.00 ml) then dried in a vacuum oven at 50° C. overnight resulting in a fluffy white powder (7.00 g, 83%). NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.47 (s, 1H), 8.06 (s, 1H), 7.45 (s, 5H), 5.81 (d, J=12.3 Hz, 2H), 4.03 (s, 3H), 3.91-3.19 (m, 8H), 2.39 (s, 3H); 13C NMR (500 MHz, DMSO-d6) δ 185.20, 169.32, 165.85, 160.75, 150.51, 146.30, 143.24, 135.53, 129.74, 129.22, 128.46, 127.34, 127.09, 123.67, 122.73, 113.94, 72.90 (d, 2JC-P=5 Hz), 57.01, 45.2 (bs), 40.8 (bs), 13.66. ES+ MS m/z (rel. intensity) 486 (MH+−H3PO4, 100).
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| Names | |
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| IUPAC name
{3-[(4-Benzoyl-1-piperazinyl)(oxo)acetyl]-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl}methyl dihydrogen phosphate
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| Other names
BMS-663068, GSK3684934
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| Identifiers | |
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3D model (JSmol)
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| ChemSpider | |
| KEGG | |
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PubChem CID
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| Properties | |
| C25H26N7O8P | |
| Molar mass | 583.498 g·mol−1 |
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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////////////////фостемсавир , فوستيمسافير , 磷坦姆沙韦 ,BMS 663068, Fostemsavir, GSK 3684934, PHASE 3, ホステムサビル;
DENAGLIPTIN
(2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile
1-[2(S)-Amino-3,3-bis(4-fluorophenyl)propionyl]-4(S)-fluoropyrrolidine-2(S)-carbonitrile
GSK-823093, 823093
811432-66-3 CAS TOSYLATE
483369-58-0 (free base)
Denagliptin (GSK-823093) having the structural formula D below is (2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, also named (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile
(D) – A –
Denagliptin is specifically disclosed in US Patent No. 7,132,443 and in WO 03/002531. In one embodiment, denagliptin is in the form of its hydrochloride salt as disclosed in Example 2 of WO 03/002531 or its tosylate salt as disclosed in WO 2005/009956. A class of this embodiment refers to denagliptin tosylate. Crystalline anhydrous denagliptin tosylate is disclosed in WO 2005/009956.
Denagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor which entered phase III clinical trials in 2006 for the treatment of type 2 diabetes at GlaxoSmithKline. Development of this compound was put on hold due to unfavorable preliminary data from preclinical long-term toxicity trials.
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http://www.google.com/patents/US7132443
Example 2
(2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride
A. 3,3-Bis(4-fluorophenyl)-3-hydroxypropanoic acid.
To an anhydrous THF (80 mL) solution of n-butyl lithium (46 mL of 2.5 M, 115 mmol) at 0° C. was added dropwise diisopropylamine (11.13 g, 115 mmol) and the solution stirred for 10 minutes. Keeping the solution at 0° C., acetic acid (2.64 g, 44 mmol) was added dropwise and the mixture stirred for 10 min and it was then heated 50° C. After 30 min a heavy precipitate had formed and the solution was allowed to cool. A solution of 4,4′-diflurobenzophenone (9.6 g, 0.044 mol) in THF (50 mL, anhydrous) was added at 0° C., and the solution stirred at room temperature overnight. Water (100 mL) and diethyl ether (100 mL) were added and the aqueous layer was separated and acidified with 1M HCl to pH 3. The organics were extracted with ethyl acetate (3×200 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a crude white solid that could be washed with cold CHCl3 to remove trace amounts of the benzophenone. The solid was dried under high vacuum yielding 5.63 g (20.2 mmol, 46% yield) of compound A as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.48–7.39 (m, 4H), 7.19–7.02 (m, 4H), 5.91 (s(br), 1H), 3.25 (s, 2H) ppm.
B. 3,3-Bis(4-fluorophenyl)acrylic acid.
To a 20% solution of sulfuric acid in acetic acid (50 mL, V/V) was compound A (5.6 g, 20.2 mmol) and the mixture stirred for 30 minutes at RT. To this solution was added H2O (500 mL) and the organics were extracted with ethyl acetate (3×150 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a white solid. The solid was dried under high vacuum yielding 4.97 g (19.1 mmol, 95% yield) of compound B as a white solid.
1H NMR (CDCl3) 400 MHz δ 7.27–7.21 (m, 2H), 7.19–7.13 (m, 2H), 7.10–6.95 (m, 4H), 6.26 (s, 1H) ppm.
C. 3,3-Bis(4-fluorophenyl)propanoic acid.
To a solution of compound B (2.5 g, 9.61 mmol) in ethyl acetate (250 mL) was added 10% palladium on carbon (50% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hours. The heterogeneous solution was filtered through celite and concentrated in vacuo to provide a yellow oil. The oil was dried under high vacuum yielding 2.40 g (9.16 mmol, 95% yield) of compound C as a yellow oil.
1H NMR (d6-DMSO) 400 MHz δ 12.08 (brs, 1H), 7.40–7.30 (m, 4H), 7.15–7.05 (m, 4H), 4.45 (t, 1H, J=8.1 Hz), 3.05(d, 2H, J=8.1 Hz) ppm.
D. (4S,5R)-3-[3,3-Bis(4-fluorophenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one.
To a THF (50 mL, anhydrous) containing compound C (2.0 g, 7.63 mmol) was added N,N-diisopropylethylamine (1.18 g, 9.16 mmol) and then the solution cooled to −78° C. To this solution was added trimethylacetyl chloride (0.97 g, 8.01 mmol) and the solution warmed to 0° C. over 1 hour. The cloudy mixture was filtered and the filtrate added slowly over 10 min to a solution of the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone at −78° C., which was prepared by the dropwise addition of n-butyl lithium (3.0 mL of 2.5 M, 7.63 mmol) to a THF (50 mL) solution of (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (1.35 g, 7.63 mmol) at −78° C. which had stirred for 10 min to provide the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone. The yellow mixture was warmed to 0° C. and quenched with H2O (50 mL) and extracted with diethyl ether (3×250 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a solid. Flash chromatography (silica gel, 20% ethyl acetate/hexanes) provided compound D. The white solid was dried under high vacuum yielding 2.31 g (5.49 mmol, 72% yield) as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 7.40–7.25 (m, 9H), 7.18–7.02 (m, 4H), 5.76 (d, 1H, J=7.6 Hz), 4.65 (m, 1H), 4.58 (t, 1H, J=7.6 Hz), 3.72 (dd, 1H, J=16.8, 7.0 Hz) 3.57 (dd, 1H, J=16.8, 7.0 Hz), 0.58 (d, 3H, J=6.7 Hz) ppm.
E. (4S,5R)-3-[(2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoyl]-4-methyl-5-[(1E,3Z)-1-methylhexa-1,3,5-trienyl]-1,3-oxazolidin-2-one.
To a THF (50 mL anhydrous) solution containing compound D (2.0 g, 4.75 mmol) at −78° C. was added dropwise potassium bis(trimethylsilyl)amide (10.0 mL of 0.5 M toluene solution, 4.98 mmol). After stirring for 10 min 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) (1.84 g, 5.94 mmol) in THF (10 mL, anhydrous) was added in one portion. After 3 minutes acetic acid was added (1.31 g, 21.8 mmol) at −78° C. and then the reaction quickly warmed to 30° C. and stirred for 1 hr at that temperature generating a light yellow solution. To this solution was added H2O (100 mL) and the organics were extracted with ethyl acetate (500 mL). After washing with sat NaHCO3 (100 mL) and drying over MgSO4 the solvent was reomved in vacuo yielding a yellow oil. Column chromatography (ethyl acetate/hexanes 1:9) provided compound E as a white solid. HPLC showed a single diastereoisomer. The white solid was dried under high vacuum yielding 1.71 g (3.70 mmol, 78% yield) as a white solid.
1H NMR (CDCl3) 400 MHz δ 7.42–7.35 (m, H), 7.25–7.18 (m, H), 7.10–7.06 (m, 2H), 7.05–6.92 (m, 2H), 5.95 (d, 1H, J=10.8 Hz), 5.05 (d, 1H, J=7.1 Hz), 4.60 (d, 1H, J=10.8 Hz), 4.38 (m, 1H), 0.95 (d, 3H, J=6.8 Hz) ppm.
F. (2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoic acid.
To a THF/H2O (4:1, 50 mL) solution of compound E (1.5 g, 3.25 mmol) at 0° C. was added a solution of lithium hydroxide (0.272 g, 6.49 mmol) in hydrogen peroxide (1.50 mL of 30% soln in H2O, 48.75 mmol). The mixture was stirred at 0° C. for 1 hr and then quenched with Na2SO4 (6.3 g, 50 mL of 1.0 M solution in H2O). The THF was removed in vacuo and the solution acidified to pH 1 with 6.0 M HCl at 0° C. The organics were extracted with ethyl acetate (2×200 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a clear oil. Column chromatography (EtOAc/hexanes/acetic acid 50:50:1) provided compound F as a white solid. The solid was dried under high vacuum yielding 0.78 g (2.60 mmol, 80% yield) as a white solid.
1H NMR (CDCl3) 400 MHz δ 9.60(s(br), 1H), 7.25–7.10 (m, 4H), 7.10–6.95 (m, 4H), 4.50 (d, 2H, J=8.6 Hz) ppm.
G. (2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoic acid.
To an ethyl acetate (250 mL) solution of compound F (1.5 g, 4.95 mmol) was added 10% palladium on carbon (10% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hr. The heterogeneous solution was filtered through celite (1 g) and the filtrate concentrated in vacuo to provide a clear oil. The oil was dried under high vacuum yielding 1.30 g (4.70 mmol, 95% yield) of compound G as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 10.2(s(br), 1H), 7.38–7.27(m, 4H), 7.08–6.98 (m, 4H), 4.25 (d, 1H, J=8.3 Hz), 3.95 (d, 1H, J=8.3 Hz) ppm.
H. (2S)-2-[(tert-Butoxycarbonyl)amino]-3,3-bis(4-fluorophenyl)propanoic acid.
To a CH2Cl2 (150 mL) solution containing compound G (1.30 g, 4.69 mmol) was added triethylamine (2.37 g, 23.4 mmol) and di-tert-butyl dicarbonate (1.23 g, 5.63 mmol). After stirring for 12 hr H2O (50 mL) and CH2Cl2 (300 mL) were added and the solution acidified to pH 3 with 1.0 M HCl. Separation of the ethyl acetate layer followed by drying over MgSO4 and removal of the solvent in vacuo yielded a clear oil. The oil was dried under high vacuum yielding 1.68 g (4.4 mmol, 95% yield) of compound H as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.35–7.22 (m, 4H), 7.15–6.95 (m, 4H), 4.78 (t, 1H, J=8.9 Hz), 4.25 (d, 1H, J=8.9 Hz), 3.05 (m, 1H), 1.20 (s, 3H), 1.15 (s, 6H) ppm.
I. (2S,4S)-1-[(2S)-2-(tert-Butoxycarbonyl)amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile.
To a DMF solution (25 mL anhydrous) was compound H (1.0 g, 2.65 mmol) and HATU (1.0 g, 2.65 mmol). To this solution was added N,N-diisopropylethylamine (0.462 mL, 2.65 mmol) and after 30 min (2S, 4S)-4-fluoro-2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate (0.619 g, 2.12 mmol) and additional N,N-diisopropylethylamine (0.37 mL 2.12 mmol) were added. This solution was allowed to stir at RT for 12 hr and then saturated sodium bicarbonate (100 mL) was added. The resulting gummy mixture was extracted with ethyl acetate (3×100 mL) and the organics were washed with saturated NaCl (50 mL) followed by drying over MgSO4. Filtration and removal of the solvent in vacuo yielded a clear oil. The oil was chromatographed on silica gel (hexanes/EtOAc 4:1) to provide a white solid. The solid was dried under high vacuum yielding 815 mg (1.72 mmol, 65% yield) of compound I as a white solid.
1H NMR (CDCl3) 400 MHz δ 7.38–7.32 (m, 2H), 7.21–7.15 (m, 2H), 7.12–6.98(m, 4H), 5.15 (d, 1H, J=51 Hz), 5.03 (d, 1H, J=8.9 Hz, 4.89 (d, 1H, J=11.2 Hz), 4.86 (d, 1H, J=8.9 Hz), 4.40 (d, 1H, J=11.2 Hz), 3.83 (ddd, 1H, J=36.8, 12.1, 3.7 Hz), 3.05 (d, 1H, J=12.2 Hz), 2.62 (t, 1H, J=15.3 Hz), 2.25 (m, 1H), 1.38 (s, 9H) ppm.
J. (2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride.
To compound I (0.5 g, 1.05 mmol) was added 4.0 N HCl in 1,4-dioxane (10 mL, 40 mmol) and after 3 hr diethyl ether (100 mL) was added. The resulting precipitate was collected by filtration and after drying under high vacuum 0.41 g (1.0 mmol, 95% yield) of compound J was obtained as a white solid.
1H NMR (d6-DMSO) 400 MHz δ 8.42 (s(br), 3H), 7.72–7.66 (m, 2H), 7.38–7.32 (m, 2H), 7.25–7.19 (m, 2H), 7.06–7.0 (m, 2H), 5.38 (d, 1H, J=51 Hz), 4.91 (d, 2H, J=8.8 Hz), 4.82 (d, 1H, J=11.3 Hz), 4.41 (d, 1H, J=11.3 Hz), 3.86 (ddd, 1H, J=39.2, 12.4, 3.1 Hz), 3.45 (q, 1H, J=12.4 Hz), 2.38–2.20 (m, 2H) ppm.
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PAPER
http://pubs.acs.org/doi/full/10.1021/op900178d
A recent paper from workers at GSK describes improvements to the synthesis of Denagliptin (12). The final chemical step is Boc deprotection of (11) with p-toluenesulphonic acid (p-TSA) in isopropanol (IPA). Some isolated batches of final product contained impurities 12A (~1%), 12B (~1%), and 12C (~0.3%). Investigation showed that these three impurities were not produced during the reaction but were produced in the dryer if there was any excess p-TSA in the filter cake during drying. These impurities could be avoided by washing the filter cake with 2 volumes of IPA prior to drying.
D.E. Paterson,* J.D. Powers, M. LeBlanc, T. Sharkey, E. Boehler, E. Irdam, and M.H. Osterhout (GlaxoSmithKline), Org. Process. Res. Dev.,2009, 13(5), 900-906.
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http://www.google.com.ar/patents/US7462641?cl=pt-PT
(2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt
EXAMPLE 1Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt, Form 1a) Preparation of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide
A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min.
The solid was collected by filtration, washed with heptane (260 mL, 2 vol), and then dried under vacuum at approximately 50° C. to constant weight. Yield: 88-90%.
b) Preparation of (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid
The reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide (116 g, 1 wt, 1 eq.), isopropyl acetate (578 mL, 5 vol), and pyridine (88 mL, 0.8 vol, 2.2 eq). The resulting slurry was stirred at approx. 20° C. Trifluoroacetic anhydride (77 mL, 1.0 wt, 1.1 eq.) was added over at least 30 minutes, maintaining the temperature at approx. 20° C. The reaction solution was stirred an additonal 1 hour at approx. 20° C. Water (578 mL, 5 vol) was added slowly, and the reaction mixture was stirred for 15 minutes. The stirring was stopped, the layers were allowed to separate, and the aqueous (lower) layer was discarded. The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume. The reaction was diluted back up to 5 volumes with isopropyl acetate. The reactor contents were cooled to 20° C., and the reactor was charged with p-toluenesulfonic acid (94 g, 0.8 wt, 1 eq). The reaction was stirred for 2 hours, and GC analysis at this point should show complete consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide. The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added. The reaction was concentrated to a final volume of 4 volumes. The reaction was cooled to 0° C. and held for 30 minutes. The solids were collected by filtration, washed with isopropyl alcohol (1 vol), and then dried under vacuum at approx. 50° C. to constant weight. Yield: 68-71%.
c) Preparation of tert-Butyl{(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate
A reactor was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (400 g, 1 wt, 1 eq.), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid (307.7 g, 0.77 wt, 1.01 eq.), O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexaflurophosphate [i.e. HATU] (408 g, 1.02 wt, 1.01 equiv.), and DMF (2.8L, 7 vol). The mixture was cooled to approximately 0° C. Hunig’s base (376 mL, 0.94 vol, 2.04 equiv.) was added over at least 30 minutes. The mixture was heated to approximately 25° C. and was stirred at this temperature until the reaction was complete (ca. 3 hours). MTBE (2.8L mL, 7 vol) was added, followed by water (2L, 5 vol) over at least 30 minutes to quench the reaction. The aqueous phase was extracted with MTBE (1.2L, 3 vol). The combined organic phases were washed with water (2L, 5 vol). The organic phase was concentrated under vacuum to 3 volumes, and ethanol (1.6L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes, and ethanol (1.6 L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes. Added ethanol (2L, 5 vol). The ethanol solution of tert-Butyl {(1 S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamatewas used directly in the next step.
d) Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt. Form 1
A 10L reactor equipped with overhead stirring was charged with a slurry of tert-Butyl {(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate (500 g, 1 wt, 1 eq) in ethanol (3.5L, 7 vol). To this solution was added para-toluenesulfonic acid (403g, 0.806 wt, 2 eq). This solution was heated to 60° C., and was allowed to stir at this temperature for 12 hours. The reaction mixture was cooled to 5° C. and was stirred at this temperature for 30 minutes. The solids were collected by filtration, washed with ethanol (2×1 L), and dried to constant weight in a 50° C. vacuum oven. Yield: 70-80% over 2 steps.
………………….
Augustyns, K. et al., “The Unique Properties of Dipeptidyl-Peptidase IV (DPP IV/CD26) and the Therapeutic Potential of DPP IV Inhibitors,” Current Medicinal Chemistry, V6, N4, 1999, pp. 311-327.
| US7132443 * | 26 Jun 2002 | 7 Nov 2006 | Smithklinebeecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
| WO2003002531A2 | 26 Jun 2002 | 9 Jan 2003 | Curt Dale Haffner | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
……………………..
DIABETES
MURAGLITAZAR(CAS-No. 331741-94-7), ROSIGLITAZONE (CAS-NO. 122320-73-4), PIOGLITAZONE (CAS-No. 111025-46-8), RAGAGLITAZAR(CAS-No. 222834-30-2), FARGLITAZAR(CAS-No. 196808-45-4), TESAGLITAZAR(CAS-No. 251565-85-2), NAVEGLITAZAR(CAS-No. 476-436-68-7), NETOGLITAZONE (CAS-NO. 161600-01-7), RIVOGLITAZONE (CAS-No. 185428-18-6), K-111 (CAS-No. 221564-97-2), GW-677954 (CAS-No. 622402-24-8), FK-614 (CAS-No 193012-35-0) and (−)-Halofenate (CAS-No. 024136-23-0).
| TABLE 1 | |
| INN or Research | |
| Code | Structure/Chemical Name |
| BIM-51077 | L-histidyl-2-methylalanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L- |
| aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L- | |
| alanyl-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L- | |
| lysyl-2-methylalanyl-L-argininamide | |
| EXENATIDE | L-histidylglycyl-L-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-leucyl- |
| L-seryl-L-lysyl-glutaminyl-L-methionyl-L-glutamyl-L-glutamyl-L-glutamyl-L-alanyl-L-valyl-L- | |
| arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L- | |
| asparaginylglyclglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L- | |
| serinamide | |
| CJC-1131 | L-histidyl-D-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha- |
| aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L- | |
| alanyl-L-lysyl-L-alpha-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl- | |
| L-lysylglycyl-L-arginyl-N6-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- | |
| yl)propionamido]ethoxy]ethoxy]acetyl]-L-lysin-amide | |
| LIRAGLUTIDE | L-histidyl-L-alanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L- |
| valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L-alanyl-Nepsilon- | |
| (Nalpha-hexadecanoyl-gamma-L-glutamyl)-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl- | |
| L-tryptophyl-L-leucyl-L-valyl-L-arginyl-glycyl-L-arginyl-glycine | |
| ZP-10 | H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe- |
| Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2 | |
| TOLBUTAMIDE |
 |
| TOLAZAMIDE |
 |
| GLIPIZIDE |
 |
| CARBUTAMIDE |
 |
| GLISOXEPIDE |
 |
| GLISENTIDE |
 |
| GLIBORNURIDE |
 |
| GLIBENCLAMIDE |
 |
| GLIQUIDONE |
 |
| GLIMEPIRIDE |
 |
| GLICLAZIDE |
 |
| METFORMIN |
 |
| ACARBOSE |
 |
| MIGLITOL |
 |
| VOGLIBOSE |
 |
| MURAGLITAZAR |
 |
| ROSIGLITAZONE |
 |
| PIOGLITAZONE |
 |
| RAGAGLITAZAR |
 |
| FARGLITAZAR |
 |
| TESAGLITAZAR |
 |
| NAVEGLITAZAR |
 |
| NETOGLITAZONE |
 |
| RIVOGLITAZONE |
 |
| K-111 |
 |
| GW-677954 |
 |
| FK-614 |
 |
| (−)-Halofenate |
 |
| REPAGLINIDE |
 |
| NATEGLINIDE |
 |
| MITIGLINIDE |
 |
| SITAGLIPTIN |
 |
| SAXAGLIPTIN |
 |
| VILDAGLIPTIN |
 |
| DENAGLIPTIN |
 |
| P32/98 |
 |
| NVP-DPP-728 |
 |
| SILDENAFIL |
 |
| VARDENAFIL |
 |
| TADALAFIL |
 |
| PRAMLINTIDE | L-lysyl-L-cysteinyl-L-asparaginyl-L-threonyl-L-alanyl-L-threonyl-L-cysteinyl-L-alanyl-L-threonyl- |
| L-glutaminyl-L-arginyl-L-leucyl-L-alanyl-L-asparaginyl-L-phenylalanyl-L-leucyl-L-valyl-L-histidyl- | |
| L-seryl-L-seryl-L-asparaginyl-L-asparaginyl-L-phenylalanylglycyl-L-prolyl-L-isoleucyl-L-leucyl-L- | |
| prolyl-L-prolyl-L-threonyl-L-asparaginyl-L-valylglycyl-L-seryl-L-asparaginyl-L-threonyl-L- | |
| tyrosinamide, cyclic (2−>7)disulfide | |
| ETOMOXIR |
 |
| HMR-1426 |
 |
| CETILISTAT |
 |
| SIBUTRAMINE |
 |
Additional information with regard to the preparation, suitable dosage forms and dose ranges of the glucagon-like-peptide-1 receptor agonists listed in Table 1 can be found in the following patents/patent applications: WO0334331, EP0981611, EP1180121, WO9808871 and WO0104156.
Dutogliptin tartrate
Syn name: 1-[N-[3(R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid L-tartrate
Cas number: 890402-81-0
Molecular Formula: C14H26BN3O9
Molecular Weight: 391.18
DUTOGLIPTIN
[1-[2-(Pyrrolidin-3-ylamino)acetyl]pyrrolidin-2-yl]boronic Acid; [(2R)-1-[2-[[(3R)-Pyrrolidin-3-yl]amino]acetyl]pyrrolidin-2-yl]boronic acid
C10H20BN3O3, 241.0951
852329-66-9
clinical trials
http://clinicaltrials.gov/search/intervention=Dutogliptin
PHX-1149 is a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor which had been in phase III clinical trials at Phenomix and Forest for the oral, once-daily treatment of type 2 diabetes.
In 2008, the compound was licensed to Forest by Phenomix in North America for development and commercialization; however this license agreement was terminated in 2010. In 2009, the compound was licensed to Chiesi by Phenomix for development and commercialization for the treatment of diabetes type 2 in Europe, Brazil, the Russian Federation and all other members of the Commonwealth of Independent States, Turkey and Northern Africa. Phenomix ceased operations in 2010.
………………………….
http://www.google.com/patents/WO2010107809A2?cl=en
or
http://www.google.com/patents/US20100240611?cl=en
The enzyme dipeptidyl peptidase IV (DPP-IV) is a member of the dipeptidyl peptidase family, which cleaves N-terminal dipeptide residues from proteins, particularly where the dipeptide includes an N-terminal penultimate proline or alanine residue. DPP-IV is believed to be involved in glucose control, as its peptidolytic action inactivates the insulotropic peptides glucagon-like peptide I (GLP-I) and gastric inhibitory protein (GIP).
Inhibition of DPP- IV, such as with synthetic inhibitors in vivo, can serve to increase plasma concentrations of GLP-I and GIP, and thus improve glycemic control in the body. Such synthetic inhibitors would therefore be useful in the treatment of diabetes mellitus and related conditions. Certain such selective DPP-IV inhibitors have been developed, as are disclosed in U.S. Patent 7,317,109, U.S. Patent 7,576,121, U.S. Application Publication Nos. 2007/0060547, 2007/0185061, 2007/0299036, 2008/0182995, 2008/0300413, 2006/0264400, and 2006/0264401, and in International Applications WO2008/027273 and WO2008/144730, the contents of which are incorporated herein by reference. Inhibition of DPP-IV by compounds of the structure of formula (I) is disclosed therein:
Example 1 – Synthesis of (R)-N-( 1 , 1 -Dimethylethoxycarbonyl)(pyrrolidine-2-yl)boronic Acid.
An oven dried 1 L three neck round bottom flask equipped with an overhead stirrer, addition funnel and internal thermocouple was charged with (IS, 2S)-Dimethyl-bis(3,3- dimethylbutyl)cyclohexane-l,2-diamine (approx. 50 g, 161.23 mmol, 1.2 eq), BOC-pyrrolidine (approx. 23.55 ml, 134.35 mmol, 1 eq) and dry toluene (approx. 500 ml) under inert atmosphere. The clear colorless solution was cooled to “ 78° C and a solution of sec-BuLi (approx. 115.16 ml of a 1.4 solution in cyclohexane, 161.23 mmol, 1.2 eq) was added slowly via dropping funnel over approx. 10 minutes (the temperature of the reaction mixture was maintained between approx. – 780C and -650C). The light orange colored solution was stirred for 3.5 hours at approx. -780C, which was then followed by the addition of a solution of trimethylborate (approx. 45.06 ml, 403.05 mmol, 3 eq) in toluene (approx. 75 ml) via dropping funnel over 30 minutes while maintaining the temperature below -650C. The reaction mixture was warmed slowly to room temperature, and stirred for 16 hours at room temperature. The reaction mixture was added into an aqueous sodium hydroxide solution (approx. 670 ml of 2.0 M solution, 1340 mmol, 10 eq) and the resulting cloudy mixture was stirred for 30 minutes before allowing layers to separate. The aqueous phase (product) was transferred to a receiver and backwashed with toluene (approx. 100 ml). The organic phases (chiral amine ligand) were transferred to a receiver for later isolation. The aqueous phase was acidified to pH 5-6 by slow addition of HCl {cone), then extracted with EtOAc (approx. 3 x 500 ml). The organic extracts were combined, dried over Na2SO4 and concentrated until a final volume of approximately 100 ml. Heptane (approx. 300 ml) was added and the concentrated mixture was stirred at room temperature overnight (approx. 15 hours). The resulting white precipitate was filtered and the filter cake was washed with cold heptane. The product was dried at room temperature under vacuum to yield (R)- (pyrrolidine-2-yl)boronic acid (approx. 20.31 g, 94.44 mmol, 70.27 %) as a white solid. [α]25D – 72.5 (c 1, DCM); 94-95 % ee (% ee was determined through chiral HPLC); 1H NMR (400 MHz, D2O) δ 3.40-3.50 (IH), 3.20- 3.30 (IH), 2.90-3.00 (IH), 2.10 (IH), 2.00 (IH), 1.85 (IH), 1.72 (IH), 1.45-1.48 (9H); m/z (ES+) 216.06.
Example 2 – Isolation of the chiral ligand ((1S, 2S)-Dimethyl-bis(3,3-dimethyl butyl) cyclohexane- 1 ,2-diamine)
Water (approx. 300 ml) was added to the first organic extract from the previous workup and cooled to 0° C the mixture was acidified to pH 3 by slow addition of HCl. The resulting cloudy mixture was stirred vigorously before allowing layers to separate. The aqueous phase (product) was transferred to a receiver and backwashed with toluene (approx. 100 ml). The aqueous phase was stirred at O0C and the pH of the solution was adjusted to 12-13 by the addition of sodium hydroxide. The mixture was extracted with toluene (approx. 3 x 500 ml) and the combined organic phases were concentrated under reduced pressure to give the crude chiral diamine (approx. 48.32 g, 155.57 mmol, 96.5%) as light yellow oil. Further purification by vacuum distillation (approx. 120-1300C, house vacuum) yielded the chiral diamine as a colorless oil (approx. 45.57 g, 146.72 mmol) in 91% recovery).Example 3 – Synthesis of (R)-N-(I, l-dimethylethoxycarbonyl)-pinanediol-(Pyrrolidin-2-yl) boronate
A solution of (R)-Pyrrolidine boronic acid (approx. 300 mg, 1.39 mmol) in isopropyl acetate (approx. 10 ml) was treated with (+)-pinanediol (approx. 236.35 mg, 1.39 mmol, 1 eq) and Na2SO4 (approx. 203.25 mg, 1.39 mmol, 1 eq). After 24 hr, the solvent was evaporated to give crude boronic ester (approx. 475.55 mg, 1.36 mmol, 98 %) as a clear oil: 98-99 % de via chiral HPLC; 1U NMR (400 MHz, CDCl3) δ 4.32 (IH), 3.47 (IH), 3.41-3.31 (2H), 3.22-3.05 (IH), 2.38- 2.30 (IH), 2.20-1.75 (8H), 1.45 (9H), 1.41 (3H), 1.28 (3H), .85 (3H); m/z (ES, M+l) 350.28.Example 4 – (R)-N-(Pyrrolidine-2-yl)-pinacol boronate
To a solution of pyrrolidine boronic acid (approx. 456 mg, 2.12 mmol) in isopropyl acetate
(approx. 15 ml) was added pinacol (approx. 251 mg, 2.12 mmol, 1 eq) and Na2SO4 (approx. 310 mg, 2.12 mmol, 1 eq). The mixture was stirred for 24 hr and the solvent was evaporated to yield crude pinacol boronate. The residue was triturated with EtOAc/hexane (approx. 1 : 10) at RT for 1 hr then filtered to give the pinacol boronate (approx. 611 mg, 2.06 mmol, 97 %) as a white solid: . 1H NMR (400 MHz, CDCl3) δ 3.40-2.95 (3H), 1.95-1.50 (4H), 1.40 (9H), 1.20 (12H); m/z (ES+) 298.21. Removal of the Boc-protecting group was achieved by dissolving the white solid pinacol boronate in dry ether (approx. 15 ml), cooling to 0° C in an ice bath followed with addition of 1.5 eq of HCl in dioxane After 8 hours, the solvent was evaporated then triturated in hexane for 1 hr. The white precipitate was filtered and dried to yield the acid salt (approx. 472 mg, 2.02 mmol, 98 %): 1HNMR (CDCl3) δ 3.48 (IH), 3.36 (IH), 3.21 (IH), 2.21 (IH), 2.03 (2H), 1.95 (IH), 1.35 (12H); m/z (ES M+l) 198.21.
Example 5 – Synthesis of (R)-3-(Benzyloxycarbonyl-{2-oxo-2-[(R)-2-((lS,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^'”]dec-4-yl)-pyrrolidin-l-yl]-ethyl}-amino)- pyrrolidine- 1-carboxylic acid benzyl ester
A mixture of (R)-3-(benzyloxycarbonyl-carboxymethyl-amino)-pyrrolidine- 1-carboxylic acid benzyl ester dicyclohexylamine salt) (approx. 300.Og, 0.505mol), water (approx. 1.5L), 2M aqueous sulfuric acid (approx. 0.75L, 1.5mol) and toluene (approx. 2L) was stirred in a 1OL reactor at room temperature for 15 min. After settling the layers were separated. The aqueous layer was stirred with toluene (approx. 1.0L) for 15 min, and the layers were separated. The combined organic layers were washed with water (approx. 1.5L), and concentrated under vacuum at 450C to 1.5L. To this solution was added N-methylmorpholine (approx. 55.4 mL, 0.505mol) and this mixture was added to a cold solution (approx. 0°-5°C) of ethyl chloroformate (approx. 48.1 mL, 0.505mol) in toluene (approx. 1.0L). The reaction mixture was stirred at 0° – 50C for 15 min and solid (2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02‘6]dec-4-yl)-pyrrolidine hydrochloride) (approx. 144.4g, 0.505mol) was added in one portion followed by addition of N- Methylmorpholine (approx. 110.8 mL, l.Olmol). The mixture was stirred for 30 min at 0°-5°C, and allowed to warm to 20°-25°C. Stirring was continued for an additional 2.5 h. Water (approx. 2.0L) was then added, and the mixture was stirred for an additional 15 min. The layers were separated and the organic layer was subsequently washed with 0.85M aqueous sodium bicarbonate solution (approx. 1.2L), water (approx. 2.0L), and 0.065M citric acid solution (approx. 1.5L). Toluene solution was concentrated under vacuum at 450C, to give 287.3 g (approx. 88.4%) of the title compound. 1H NMR (400 MHz, CDCl3, ppm): mixture of rotomers, 7.35-7.25 (10H,m); 5.22- 4.99 (4H,m); 4.60 (IH, d); 4.22 (IH, dd); 4.11-3.65 (3H, m); 3.60-3.00 (6H, m); 2.32-1.91 (8H, m); 1.89-1.67 (4H, m); 1.42-1.18 (6H, m); 0.84-0.72 (3H, m); m/z (M+H)=644. Example 6 – Synthesis of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.0 ‘ ]dec-4-yl)-pyrrolidin- 1 -yl]-ethanone
a) THF solvateA solution of (R)-3-(Benzyloxycarbonyl-{2-oxo-2-[(R)-2-((l S,2S,6R,8S)-2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.02‘”]dec-4-yl)-pyrrolidin- 1 -yl] -ethyl }-amino)-pyrrolidine- 1 – carboxylic acid benzyl ester (approx. 4.76 g, 7.4 mmol) in toluene (approx. 60 mL) was diluted with methanol (approx. 60 mL). 10% Pd/C (wet, 500 mg) was added, and the mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through celite and washed with methanol (approx. 10 mL). The solution was then concentrated under vacuum to dryness. The residue was dissolved in THF (approx. 10 mL) at 4O0C and crystallized overnight at -1O0C to -15°C. Crystals were filtered, washed with cold THF (approx. 3 mL), and dried under vacuum for 5 h to yield 1.9 g (approx. 68.5%) of the title compound. 1H NMR (400 MHz, D2O, 1 drop TFA), 64.18 – 4.89 (m, IH), 3.93 – 3.85 (m, IH), 3.77 (s, 2H), 3.55 (dd, IH)5 3.45 -3.38 (m, 4H), 3.35 – 3.25 (m, 2H), 3.24 – 3.05 (m, 3H), 2.93 (t, IH), 2.33 – 2.24 (m, IH), 2.15 – 1.42 (m, 16H), 1.09 (s, 3H), 0.94 (s, 3H), 0.78 (d, IH), 0.50 (s, 3H). m/z (ES+) = 376.30.
Thermogravimetric analysis of THF solvate of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-
((lS,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02‘6]dec-4-yl)-pyrrolidin-l-yl]- ethanone was performed as is shown in Figure 5.
X-Ray Diffractogram of THF solvate of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02‘6]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 6. b) Non-solvate
A solution of (3-(Benzyloxycarbonyl-{2-oxo-2-[2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02‘6]dec-4-yl)-pyrrolidin-l-yl]-ethyl}-amino]-pyrrolidine-l-carboxylic acid benzyl ester) (approx. 20.Og, 31.Ommol) in toluene (approx. 8OmL) was diluted with methanol (approx. 20 mL). 10% Pd/C (2g, wet) was added, and the mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through celite and the filter bed was washed with a mixture of toluene (approx. 2OmL) and methanol (approx. 4 mL). The solution was concentrated to 8OmL at 30 -35 0C under vacuum (approx. 90 to 120 mBar). THF (approx. 10OmL) was added and the solution was concentrated to 12OmL at 30 -35 0C under vacuum (approx. 90 to 120 mBar). The mixture was stirred at 35 0C for Ih, resulting in crystallization. The mixture was cooled to 0 0C and held at that temperature for 2h. Crystals were isolated by filtration, washed with a cold mixture of toluene (approx. 20 mL) and THF (approx. 5 mL), and dried under vacuum at 35 0C for 16 h to yield 9.11 g (approx. 24.3 mmol, 78%) of the title compound as a white solid.1H NMR (400 MHz, D20, 1 drop TFA), δ 4.34 (dd, IH, J= 9, 2 Hz), 4.08 (m, IH), 3.99 (s, 2H), 3.74 (dd, IH, J= 13, 8 Hz), 3.52 -3.29 (m, 6H), 3.12 (t, IH, J= 8 Hz), 2.47 (m, IH), 2.27 (m, IH), 2.19 – 2.06 (m, 2H), 2.02 – 1.84 (m, 6H), 1.67 (m, 2H), 1.30 (s, 3H), 1.15 (s, 3H), 1.00 (d, IH, J= 11 Hz), 0.71 (s, 3H). m/z (ES+) = 376.30.
Thermogravimetric analysis of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^'”]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 7.
X-Ray Diffractogram of2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9-trimethyl-
3,5-dioxa-4-bora-tricyclo[6.1.1.0 ‘ ]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 8.
Example 7 – Synthesis of Dutogliptin Tartrate
A round bottom flask equipped with a magnetic stirrer was charged with 2-(Pyrrolidin-3- ylamino)- 1 -[2-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0]dec-4-yl)-pyrrolidin-l-yl]- ethanone (approx. l:l-Pinanediol borane / THF complex; 2.98 g, 6.67 mmol, leq), (L)-tartaric acid (approx. 1.00 g, 6.67 mmol, 1 eq), and H2O (approx. 15 mL). The mixture was allowed to stir for 1 hour then tert-Butyl methyl ether (approx. 15 ml) and (i?)-N-(l,l- dimethylethoxycarbonyl)(pyrrolidine-2-yl)boronic acid (approx. 1.46 g, 6.80 mmol, 1.02 eq) were added. The bi-phasic mixture was allowed to stir for 20 hours at room temperature before separating the layers. The aqueous phase backwashed with tert-butyl methyl ether (approx. 15 ml) and the organic layers were combined. Lyophilization of the aqueous layer provided dutogliptin tartrate as a white solid (approx. 2.60 g, 6.65 mmol, 99.7%): 1H NMR (400 MHz, D2O, one drop of TFA) δ 4.48 (2H), 3.95-3.88 (IH), 3.81 (2H), 3.59-3.54 (IH), 3.37-3.28 (2H), 3.21-3.16 (2H), 3.11-3.07 (IH), 2.82-2.78 (IH), 2.37-2.28 (IH), 2.04-1.96 (IH), 1.88-1.78 (2H), 1.71-1.60 (IH), 1.50-1.42 (IH); m/z (ES+) 241.10 (-tartrate acid).
| US20060069250 * | Sep 28, 2005 | Mar 30, 2006 | Xiaohu Deng | Synthesis by chiral diamine-mediated asymmetric alkylation |
| US20080182995 * | Oct 31, 2007 | Jul 31, 2008 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv |
| US20080300413 * | Jul 27, 2006 | Dec 4, 2008 | David Alan Campbell | Efficiently preparing boropyrrolidines and derivatives by coupling a (pyrrolidin3-yl-amino-)acetic acid and a 7,9,8-dioxaborotricyclic- (4,3,0,1(2,4))decane; protecting groups avert side reactions; antidiabetic agents |
Ragaglitazar
NNC-61-0029, (-) – DRF-2725, NN-622,
(−)DRF 2725
cas 222834-30-2
222834-21-1 (racemate)
Hyperlipidemia; Hypertriglyceridemia; Lipid metabolism disorder; Non-insulin dependent diabetes
PPAR alpha agonist; PPAR gamma agonist
(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID,
(2S)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid, DRF, 1nyx
……………………………………………………………..
J Med Chem 2001,44(16),2675
http://pubs.acs.org/doi/abs/10.1021/jm010143b
(−)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPARα and PPARγ. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.
Scheme 1 a
a (a) NaH, DMF, 0−25 °C, 12 h; (b) triethyl 2-ethoxy phosphosphonoacetate, NaH, THF, 0−25 °C, 12 h; (c) Mg/CH3OH, 25 °C, 12 h; (d) 10% aq NaOH, CH3OH, 25 °C, 6 h; (e) (1) pivaloyl chloride, Et3N, DCM, 0 °C, (2) (S)-2-phenyl glycinol/Et3N; (f) 1 M H2SO4, dioxane/water, 90−100 °C, 80 h.
Compound 6 is prepared from phenoxazine using a synthetic route shown in Scheme 1. Phenoxazine 7 upon reaction with p-bromoethoxy benzaldehyde 89 gave benzaldehyde derivative 9. Reacting 9 with triethyl 2-ethoxy phosphonoacetate afforded propenoate 10 as a mixture of geometric isomers. Reduction of 10 using magnesium methanol gave propanoate 11, which on hydrolysis using aqueous sodium hydroxide gave propanoic acid 12 in racemic form. Resolution of 12 using (S)(+)-2-phenyl glycinol followed by hydrolysis using sulfuric acid afforded the propanoic acid 6 in (−) form.
Nate, H.; Matsuki, K.; Tsunashima, A.; Ohtsuka, H.; Sekine, Y. Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. II. 2-(phenylpiperazinoalkoxyphenyl)thiazolidine-3-thiocarboxyamides and corresponding carboxamides. Chem. Pharm. Bull. 1987, 35, 2394−2411
(S)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-eth-oxypropanoic Acid (6). as a white solid, mp: 89−90 °C.
[α]D 25 = − 12.6 (c = 1.0%, CHCl3).
1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J = 7.0 Hz, 3H), 1.42−1.91 (bs, 1H, D2O exchangeable), 2.94−3.15 (m, 2H), 3.40−3.65 (m, 2H), 3.86−4.06 (m, 3H), 4.15 (t, J = 6.6 Hz, 2H), 6.63−6.83 (m, 10H), 7.13 (d, J = 8.5 Hz, 2H). Mass m/z (relative intensity): 419 (M+, 41), 197 (15), 196 (100), 182 (35), 167 (7), 127 (6), 107 (19).
Purity by HPLC: chemical purity: 99.5%; chiral purity: 94.6% (RT 27.5).
…………………………………
http://www.google.com/patents/US6608194?cl=zh
EXAMPLE 23 (−) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid:
The title compound (0.19 g, 54%) was prepared as a white solid from diastereomer [(2S-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenyl)ethylpropanamide (0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example 22. mp: 89-90° C.
[α]D 25=−12.6 (c=1.0% CHCl3)
1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J=7.02 Hz, 3H), 1.42-1.91 (bs, 1H, D2O exchangeable), 2.94-3.15 (complex, 2H), 3.40-3.65 (complex, 2H), 3.86-4.06 (complex, 3H), 4.15 (t, J=6.65 Hz, 2H), 6.63-6.83 (complex, 10H), 7.13 (d, J=8.54 Hz, 2H).
………………………..
http://www.google.com/patents/EP1049684A1?cl=en
Example 23
(S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid :
The title compound (0.19 g, 54 %) was prepared as a white solid from diastereomer [(2S- N(lS)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l- phenyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example 22. mp : 89 – 90 °C. [α]D 25 = – 12.6 (c = 1.0 %, CHC13)
*H NMR (CDC13, 200 MHz) : δ 1.16 (t, J = 7.02 Hz, 3H), 1.42 – 1.91 (bs, IH, D20 exchangeable), 2.94 – 3.15 (complex, 2H), 3.40 – 3.65 (complex, 2H), 3.86 – 4.06 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.63 – 6.83 (complex, 10H), 7.13 (d, J = 8.54 Hz, 2H).
| Patent | Submitted | Granted |
|---|---|---|
| Benzamides as ppar modulators [US2006160894] | 2006-07-20 | |
| Novel tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US2002077320] | 2002-06-20 | |
| Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US7119198] | 2006-07-06 | 2006-10-10 |
| Tricyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them [US6440961] | 2002-08-27 | |
| Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6548666] | 2003-04-15 | |
| Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6608194] | 2003-08-19 | |
| CRYSTALLINE R- GUANIDINES, ARGININE OR (L) -ARGININE (2S) -2- ETHOXY -3-{4- [2-(10H -PHENOXAZIN -10-YL)ETHOXY]PHENYL}PROPANOATE [WO0063189] | 2000-10-26 | |
| Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds [US6897199] | 2002-11-14 | 2005-05-24 |
| Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6939988] | 2005-09-06 |
WO-2014181362
Nov 13, 2014 – (WO2014181362) A PROCESS FOR THE PREPARATION OF 3-ARYL-2-HYDROXY PROPANOIC ACID COMPOUNDS …
A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds
ragaglitazar; saroglitazar
Council of Scientific and Industrial Research (India)
Process for preparing enantiomerically pure 3-aryl-2-hydroxy propanoic acid derivatives (eg ethyl-(S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate), using S-benzyl glycidyl ether as a starting material. Useful as intermediates in the synthesis of peroxisome proliferator activated receptor agonist such as glitazars (eg ragaglitazar or saroglitazar). Appears to be the first filing on these derivatives by the inventors; however see WO2014181359 (for a concurrently published filing) and US8748660 (for a prior filing), claiming synthesis of enantiomerically pure compounds.
Duvelisib
Infinity and AbbVie partner to develop and commercialise duvelisib for cancer
INK 1197; IPI 145; 8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone
1(2H)-Isoquinolinone, 8-chloro-2-phenyl-3-((1S)-1-(9H-purin-6-ylamino)ethyl)-
8-Chloro-2-phenyl-3-((1S)-1-(7H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one
(S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
UNII-610V23S0JI; IPI-145; INK-1197;
Originator…….. Millennium Pharmaceuticals
| Molecular Formula | C22H17ClN6O | |
| Molecular Weight | 416.86 | |
| CAS Registry Number | 1201438-56-3 |
Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, to treat patients with cancer.
Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K gamma, to treat patients with cancer.
Duvelisib has shown clinical activity against different blood cancers, such as indolent non-Hodgkin’s lymphoma (iNHL) and chronic lymphocytic leukemia (CLL).
AbbVie executive vice-president and chief scientific officer Michael Severino said: “We believe that duvelisib is a very promising investigational treatment based on clinical data showing activity in a broad range of blood cancers.”
Duvelisib (IPI-145, INK-1197), an inhibitor of PI3K-delta and –gamma, originated at Takeda subsidiary Intellikine. It is now being developed by Infinity Pharmaceuticals, which began a phase III trial in November, following US and EU grant of orphan drug status for both CLL and small lymphocytic leukemia
INK-1197 is a dual phosphatidylinositol 3-Kinase delta (PI3Kdelta) and gamma (PI3Kgamma) inhibitor in phase III clinical development at Infinity Pharmaceuticals for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. The company is also carring phase II trials for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma) are currently under way.
IPI-145 is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma. The PI3K-delta and PI3K-gamma isoforms are preferentially expressed in leukocytes (white blood cells), where they have distinct and non-overlapping roles in key cellular functions, including cell proliferation, cell differentiation, cell migration and immunity. Targeting PI3K-delta and PI3K-gamma may provide multiple opportunities to develop differentiated therapies for the treatment of blood cancers and inflammatory diseases.
Licensee Infinity Pharmaceuticals is developing INK-1197. In 2014, Infinity licensed Abbvie for joint commercialization in the U.S. and exclusive commercialization elsewhere. Originator Millennium Pharmaceuticals had also been developing the compound; however, no recent development has been reported for this research. In 2013, orphan drug designations were assigned by the FDA and the EMA for the treatment of chronic lymphocytic leukemia, for the treatment of small lymphocytic lymphoma and for the treatment of follicular lymphoma.
currently enrolling patients DYNAMO™, a Phase 2 study designed to evaluate the activity and safety of IPI-145 in approximately 120 people with refractory indolent non-Hodgkin lymphoma (iNHL) and DUO™, a Phase 3 clinical study of IPI-145 in approximately 300 people with relapsed/refractory chronic lymphocytic leukemia (CLL). These studies are supported by Phase 1 data reported at the 2013 American Society of Hematology (ASH) Annual Meeting which showed that IPI-145 was well tolerated and clinically active in a broad range of malignancies, including iNHL and CLL. These studies are part of DUETTS™, a worldwide investigation of IPI-145 in blood cancers.
WO 2011008302
http://www.google.com/patents/WO2011008302A1?cl=en
Reaction Scheme 1
Reaction Scheme 2:
201 202 203
204 205
Reaction Scheme 3:
Reaction Scheme 4A:
Reaction Scheme 4B:
2
Example 14b: Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)
(compound 4904)
Scheme 27b. The synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)
(compound 4904) is described.
[00493] The compound of Formula 4904 (compound 292 in Table 4) was synthesized using the synthetic transformations as described in Examples 12 and 14a, but 2-chloro-6-methyl benzoic acid (compound 4903) was used instead of 2, 6 ,dimethyl benzoic acid (compound 4403). By a similar method, compound 328 in Table 4 was synthesized using the synthetic transformations as described starting from the 2-chloro-6-methyl m-fluorobenzoic acid.
…………………………………….
http://www.google.com/patents/WO2012097000A1?cl=en OR http://www.google.com/patents/US8809349?cl=en
Formula (I):
(I),
or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the method comprises any one, two, three, four, five, six, seven, or eight, or more of the following steps:
“Formula (I)” includes (S)-3-(l -(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one in its imide tautomer shown below as (1-1) and in its lactim tautomer shown below as (1-2):
(1-1)………………………………………………………………………………… (1-2)
[0055] FIG. 27 shows an FT-IR spectra of Polymorph Form C.
[0056] FIG. 28 shows a ‘H-NMR spectra of Polymorph Form C.
[0057] FIG. 29 shows a 13C-NMR spectra of Polymorph Form C.
Example 1
Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
Example 1A
1 2
[00563] Compound 1 (6.00 kg) was treated with 1-hydroxybenzotriazole monohydrate (HOBt»H20), triethylamine, Ν,Ο-dimethylhydroxylamine hydrochloride, and EDCI in dimethylacetamide (DMA) at
10 °C. The reaction was monitored by proton NMR and deemed complete after 2.6 hours, affording Compound 2 as a white solid in 95% yield. The R-enantiomer was not detected by proton NMR using (R)-(- ) -alpha-ace tylmandelic acid as a chiral-shift reagent.
[00564] Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H- pyran (DHP) in ethyl acetate at 75 °C for 2.6 hours. The reaction was monitored by HPLC. Upon completion of the reaction, Compound 4 was obtained as a yellow solid in 80% yield with >99% (AUC) purity by HPLC analysis.
[00565] Compound 5 (3.30 kg) was treated with thionyl chloride and a catalytic amount of DMF in methylene chloride at 25 °C for five hours. The reaction was monitored by HPLC which indicated a 97.5% (AUC) conversion to compound 6. Compound 6 was treated in situ with aniline in methylene chloride at 25 °C for 15 hours. The reaction was monitored by HPLC and afforded Compound 7 as a brown solid in 81% yield with >99% (AUC) purity by HPLC analysis. [00566] Compound 2 was treated with 2.0 M isopropyl Grignard in THF at -20 °C. The resulting solution was added to Compound 7 (3.30 kg) pre -treated with 2.3 M n-hexyl lithium in tetrahydrofuran at -15 °C. The reaction was monitored by HPLC until a 99% (AUC) conversion to Compound 8 was observed.
Compound 8 was treated in situ with concentrated HC1 in isopropyl alcohol at 70 °C for eight hours. The reaction was monitored by HPLC and afforded Compound 9 as a brown solid in 85% yield with 98% (AUC) purity and 84% (AUC) ee by HPLC analysis.
Example ID
[00567] Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at 55 °C for 1-2 hours. The batch was filtered and treated with ammonium hydroxide in deionized (DI) water to afford enantiomerically enriched Compound 9 as a tan solid in 71% yield with >99% (AUC) purity and 91% (AUC) ee by HPLC analysis.
Example 2
Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
Example 2A
[00568] To Compound 7 (20.1 g) was charged 100 mL of anhydrous THF. The resulting solution was cooled to about -10 °C and 80 mL of n-hexyl lithium (2.3 M in hexanes, 2.26 equiv.) was slowly added (e.g. , over about 20 min). The resulting solution was stirred at about -10 °C for about 20 min.
[00569] To Compound 2 (26.5 g; 1.39 equiv.) was charged 120 mL of anhydrous THF. The resulting mixture was cooled to about -10 °C and 60 mL of isopropyl magnesium chloride (2.0 M in THF, 1.47 equiv.) was slowly added (e.g. , over about 15-20 min). The resulting mixture was then stirred at about -10 °C for about 20 min. The mixture prepared from Compound 2 was added to the solution prepared from Compound 7 while maintaining the internal temperature between about -10 and about 0 °C. After the addition was complete (about 5 min), the cold bath was removed, and the resulting mixture was stirred at ambient temperature for about 1 h, then cooled. [00570] A solution of 100 mL of anisole and 33 mL of isobutyric acid (4.37 equiv.) was prepared. The anisole solution was cooled to an internal temperature of about -3 °C. The above reaction mixture was added to the anisole solution such that the internal temperature of the anisole solution was maintained at below about 5 °C. The ice bath was then removed (after about 15 min, the internal temperature was about 7 °C). To the mixture, 100 mL of 10 wt aqueous NaCl solution was rapidly added (the internal temperature increased from about 7 °C to about 15 °C). After stirring for about 30 min, the two phases were separated. The organic phase was washed with another 100 mL of 10 wt aqueous NaCl. The organic phase was transferred to a flask using 25 mL of anisole to facilitate the transfer. The anisole solution was then concentrated to 109 g. Then, 100 mL of anisole was added.
[00571] To the approximately 200 mL of anisole solution was added 50 mL of TFA (8 equiv.) while maintaining the internal temperature below about 45-50 °C. The resulting solution warmed to about 45-50 °C and stirred for about 15 hrs, then cooled to 20-25 °C. To this solution was added 300 mL of MTBE dropwise and then the resulting mixture was held at 20-25 °C for 1 h. The mixture was filtered, and the wet cake washed with approximately 50 mL of MTBE. The wet cake was conditioned on the filter for about 1 h under nitrogen. The wet cake was periodically mixed and re-smoothed during conditioning. The wet cake was then washed with 200 mL of MTBE. The wet cake was further conditioned for about 2 h (the wet cake was mixed and resmoothed after about 1.5 h). The wet cake was dried in a vacuum oven at about 40 °C for about 18 h to afford Compound 9»TFA salt in about 97.3% purity (AUC), which had about 99.1 % S- enantiomer (e.g. , chiral purity of about 99.1 %).
[00572] Compound 9»TFA salt (3 g) was suspended in 30 mL of EtOAc at about 20 °C. To the EtOAc suspension was added 4.5 mL (2.2 eq.) of a 14% aqueous ammonium hydroxide solution and the internal temperature decreased to about 17 °C. Water (5 mL) was added to the biphasic mixture. The biphasic mixture was stirred for 30 min. The mixing was stopped and the phases were allowed to separate. The aqueous phase was removed. To the organic phase (combined with 5 mL of EtOAc) was added 10 mL of 10% aqueous NaCl. The biphasic mixture was stirred for about 30 min. The aqueous phase was removed. The organic layer was concentrated to 9 g. To this EtOAc mixture was added 20 mL of i-PrOAc. The resulting mixture was concentrated to 14.8 g. With stirring, 10 mL of n-heptane was added dropwise. The suspension was stirred for about 30 min, then an additional 10 mL of n-heptane was added. The resulting suspension was stirred for 1 h. The suspension was filtered and the wet cake was washed with additional heptane. The wet cake was conditioned for 20 min under nitrogen, then dried in a vacuum oven at about 40 °C to afford Compound 9 free base in about 99.3% purity (AUC), which had about 99.2% S-enantiomer (e.g., chiral purity of about 99.2%).
Example 2B [00573] A mixture of Compound 7 (100 g, 0.407 mol, 1 wt) and THF (500 mL, 5 vol) was prepared and cooled to about 3 °C. n-Hexyllithium (2.3 M in hexanes, 400 mL, 0.920 mol, 2.26 equiv) was charged over about 110 minutes while maintaining the temperature below about 6 °C. The resulting solution was stirred at 0 ± 5 °C for about 30 minutes. Concurrently, a mixture of Compound 2 (126 g, 0.541 mol, 1.33 equiv) and THF (575 mL, 5.8 vol) was prepared. The resulting slurry was charged with isopropylmagnesium chloride (2.0 M in THF, 290 mL, 0.574 mol, 1.41 equiv) over about 85 minutes while maintaining the temperature below about 5 °C. The resulting mixture was stirred for about 35 minutes at 0 ± 5 °C. The Compound 2 magnesium salt mixture was transferred to the Compound 7 lithium salt mixture over about 1 hour while maintaining a temperature of 0 ± 5 °C. The solution was stirred for about 6 minutes upon completion of the transfer.
[00574] The solution was added to an about -5 °C stirring solution of isobutyric acid (165 mL, 1.78 mol, 4.37 equiv) in anisole (500 mL, 5 vol) over about 20 minutes during which time the temperature did not exceed about 6 °C. The resulting solution was stirred for about 40 minutes while being warmed to about 14 °C. Then, a 10% sodium chloride solution (500 mL, 5 vol) was rapidly added to the reaction. The temperature rose to about 21 °C. After agitating the mixture for about 6 minutes, the stirring was ceased and the lower aqueous layer was removed (about 700 mL). A second portion of 10% sodium chloride solution (500 mL, 5 vol) was added and the mixture was stirred for 5 minutes. Then, the stirring was ceased and the lower aqueous layer was removed. The volume of the organic layer was reduced by vacuum distillation to about 750 mL (7.5 vol).
[00575] Trifluoroacetic acid (250 mL, 3.26 mol, 8.0 equiv) was added and the resulting mixture was agitated at about 45 °C for about 15 hours. The mixture was cooled to about 35 °C and MTBE (1.5 L, 15 vol) was added over about 70 minutes. Upon completion of the addition, the mixture was agitated for about 45 minutes at about 25-30 °C. The solids were collected by vacuum filtration and conditioned under N2 for about 20 hours to afford Compound 9*TFA salt in about 97.5% purity (AUC), which had a chiral purity of about 99.3%.
[00576] Compound 9»TFA salt (100 g) was suspended EtOAc (1 L,10 vol) and 14% aqueous ammonia (250 mL, 2.5 vol). The mixture was agitated for about 30 minutes, then the lower aqueous layer was removed. A second portion of 14% aqueous ammonia (250 mL, 2.5 vol) was added to the organic layer. The mixture was stirred for 30 minutes, then the lower aqueous layer was removed. Isopropyl acetate (300 mL, 3 vol) was added, and the mixture was distilled under vacuum to 500 mL (5 vol) while periodically adding in additional isopropyl acetate (1 L, 10 vol).
[00577] Then, after vacuum-distilling to a volume of 600 mL (6 vol), heptanes (1.5 L, 15 vol) were added over about 110 minutes while maintaining a temperature between about 20 °C and about 30 °C. The resulting slurry was stirred for about 1 hour, then the solid was collected by vacuum filtration. The cake was washed with heptanes (330 mL, 3.3 vol) and conditioned for about 1 hour. The solid was dried in an about 45 °C vacuum oven for about 20 hours to afford Compound 9 free base in about 99.23% purity (AUC), which has a chiral purity of about 99.4%.
Example 3
Chiral Resolution of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9)
[00578] In some instances, (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) obtained by synthesis contained a minor amount of the corresponding (R)-isomer. Chiral resolution procedures were utilized to improve the enantiomeric purity of certain samples of (S)-3-(l-aminoethyl)-8- chloro-2-phenylisoquinolin- 1 (2H)-one.
[00579] In one experiment, Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at about 55 °C for about 1 to about 2 hours. The mixture was filtered and treated with ammonium hydroxide in deionized (DI) water to afford Compound 9 in greater than about 99% (AUC) purity, which had a chiral purity of about 91% (AUC).
[00580] In another procedure, MeOH (10 vol.) and Compound 9 (1 equiv.) were stirred at 55 ± 5 °C. D- Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for about 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. The cake was returned to the reactor and water (16 vol.) was charged. The mixture was stirred at 25 ± 5 °C. NH4OH was then charged over about 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the cake was washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9 free base with a chiral purity of about 99.0%.
Example 4
Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
[00581] A mixture of Compound 7 (1 equiv.) and anhydrous THF (5 vol.) was prepared. Separately, a mixture of Compound 2 (1.3 equiv.) and anhydrous THF (5 vol.) was prepared. Both mixtures were stirred for about 15 min at about 20 to about 25 °C and then cooled to -25 ± 15 °C. n-Hexyl lithium (2.05 equiv.) was added to the Compound 7 mixture, maintaining the temperature at > 5 °C. i-PrMgCl (1.33 equiv.) was added to the Compound 2 mixture, maintaining the temperature at > 5 °C. The Compound 2 mixture was transferred to the Compound 7 mixture under anhydrous conditions at 0 ± 5 °C. The resulting mixture was warmed to 20 ± 2 °C and held for about 1 h. Then, the reaction was cooled to -5 ± 5 °C, and 6 N HC1 (3.5 equiv.) was added to quench the reaction, maintaining temperature at below about 25 °C. The aqueous layer was drained, and the organic layer was distilled under reduced pressure until the volume was 2-3 volumes. IPA (3 vol.) was added and vacuum distillation was continued until the volume was 2-3 volumes. IPA (8 vol.) was added and the mixture temperature was adjusted to about 60 °C to about 75 °C. Cone. HC1 (1.5 vol.) was added and the mixture was subsequently held for 4 hours. The mixture was distilled under reduced pressure until the volume was 2.5-3.5 volumes. The mixture temperature was adjusted to 30 ± 10 °C. DI water (3 vol.) and DCM (7 vol.) were respectively added to the mixture. Then, NH4OH was added to the mixture, adjusting the pH to about 7.5 to about 9. The temperature was adjusted to about 20 to about 25 °C. The layers were separated and the aqueous layer was washed with DCM (0.3 vol.). The combined DCM layers were distilled until the volume was 2 volumes. i-PrOAc (3 vol.) was added and vacuum distillation was continued until the volume was 3 volumes. The temperature was adjusted to about 15 to about 30 °C. Heptane (12 vol.) was charged to the organic layer, and the mixture was held for 30 min. The mixture was filtered and filter cake was washed with heptane (3 vol.). The cake was vacuum dried at about 45 °C afford Compound 9.
[00582] Then, MeOH (10 vol.) and Compound 9 (1 equiv.) were combined and stirred while the temperature was adjusted to 55 ± 5 °C. D-Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. Water (16 vol.) was added to the cake and the mixture was stirred at 25 ± 5 °C. NH4OH was charged over 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the resulting cake washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9.
[00583] To a mixture of i-PrOH (4 vol.) and Compound 9 (1 equiv.) was added Compound 4 (1.8 equiv.), Et3N (2.5 equiv.) and i-PrOH (4 vol.). The mixture was agitated and the temperature was adjusted to 82 ± 5 °C. The mixture was held for 24 h. Then the mixture was cooled to about 20 to about 25 °C over about 2 h. The mixture was filtered and the cake was washed with i-PrOH (2 vol.), DI water (25 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford Compound 10.
To a mixture of EtOH (2.5 vol.) and Compound 10 (1 equiv.) was added EtOH (2.5 vol.) and DI water (2 vol.). The mixture was agitated at about 20 to about 25 °C. Cone. HC1 (3.5 equiv.) was added and the temperature was adjusted to 35 ± 5 °C. The mixture was held for about 1.5 h. The mixture was cooled to 25 ± 5 °C and then polish filtered to a particulate free vessel. NH4OH was added, adjusting the pH to about 8 to about 9. Crystal seeds of Form C of a compound of Formula (I) (0.3 wt ) were added to the mixture which was held for 30 minutes. DI water (13 vol.) was added over about 2 h. The mixture was held for 1 h and then filtered. The resulting cake was washed with DI water (4 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned for about 24 h and then DCM (5 vol.) was added. This mixture was agitated for about 12 h at about 20 to about 25 °C. The mixture was filtered and the cake washed with DCM (1 vol.). The cake was conditioned for about 6 h. The cake was then vacuum-dried at 50 ± 5 °C. To the cake was added DI water (10 vol.), and i-PrOH (0.8 vol.) and the mixture was agitated at 25 ± 5 °C for about 6 h. An XRPD sample confirmed the compound of Formula (I) was Form C. The mixture was filtered and the cake was washed with DI water (5 vol.) followed by n-heptane (3 vol.). The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford a compound of Formula (I) as polymorph Form C. Example 5
Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
Example 5A
[00584] Compound 9 (2.39 kg) was treated with Compound 4 and triethylamine in isopropyl alcohol at 80 °C for 24 hours. The reaction was monitored by HPLC until completion, affording 8-chloro-2-phenyl-3- ((lS)-l-(9-(tetrahydro-2H^yran-2-yl)-9H^urin-6-ylamino)ethyl)isoquinolin-l(2H)-one (compound 10) as a tan solid in 94% yield with 98% (AUC) purity by HPLC analysis.
[00585] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (compound 10) (3.63 kg) was treated with HC1 in ethanol at 30 °C for 2.3 hours. The reaction was monitored by HPLC until completion, and afforded a compound of Formula (I) as a tan solid in 92% yield with >99% (AUC) purity and 90.9% (AUC) ee by HPLC analysis.
Example 5B
[00586] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (0.72 mmol), 6-chloro- 9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA
(279 mg, 2.16 mmol) were dissolved in «-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-l(2H)-one (Compound 10), as a white solid (60% yield). [00587] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (Compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHC03 aqueous solution and the pH was adjusted to about 7-8. The mixture was extracted with CH2C12 (50 mL x 3), dried over anhydrous Na2S04, and filtered. The filtrate was concentrated in vacuo, and the residue was recrystallized from ethyl acetate and hexanes (1 : 1). The solid was collected by filtration and dried in vacuo to afford the product (S)-3-(l-(9H-purin-6-ylamino) ethyl)-8-chloro-2-phenylisoquinolin- l(2H)-one (Formula (I)) (90% yield) as a white solid as polymorph Form A.
Example 5C
[00588] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) and 6-chloro-9- (tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82 °C for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35 °C to remove the tetrahydropyranyl group to yield (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.
Example 6
Synthesis of (S)-3-(l-(9H^urin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
[00589] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (150 g; 90% ee) and 6- chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5 °C, held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25 °C for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48 °C for two and half days to give 227 g (90.1 %) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94 ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.
[00590] The intermediate (Compound 10) (200 g) was slurried in an ethanol (900 mL; 4.5 vol) / water (300 mL; 1.5 vol) mixture at 22 °C followed by addition of cone. HC1 (300 mL; 1.5 vol) and holding for one and half hours at 25-35 °C. Addition of HC1 resulted in complete dissolution of all solids producing a dark brown solution. Ammonium hydroxide (260 mL) was added adjusting the pH to 8-9. Product seeds of polymorph Form C (0.5 g) (Form A seeds can also be used) were then added and the batch which was held for ten minutes followed by addition of water (3 L; 15 vol) over two hours resulting in crystallization of the product. The batch was held for 3.5 hours at 20-25 °C and then filtered. The cake was washed with water (1 L; 5 vol) followed by heptane (800 mL; 4 vol) and vacuum dried at 52 °C for 23 hours to give 155.5 g (93.5%) of product with 99.6% (AUC) purity and 93.8% ee (chiral HPLC).
Example 7
-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
[00591] A mixtue of isopropanol (20.20 kg, 8 vol.), Compound 9 (3.17 kg, 9.04 mol, 1 eq.), Compound 4 (4.61 kg, 16.27 mol, 1.8 eq.) and triethylamine (2.62 kg, 20.02 mol, 2.4 eq.) was prepared and heated to an internal temperature of 82 ± 5 °C. The mixture was stirred at that temperature for an additional about 24 h. The temperature was adjusted to 20 ± 5 °C slowly over a period of about 2 h and the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a Sharkskin paper. The filter cake was rinsed sequentially with IPA (5.15 kg, 3 vol.), purified water (80.80 kg, 25 vol.) and n-heptane (4.30 kg, 2 vol.). The cake was further dried for about 4 days in vacuo at 50 ± 5 °C to afford Compound 10.
[00592] To a mixture of ethanol (17.7 kg, 5 vol.) and Compound 10 (4.45 kg, 8.88 mol. 1.0 eq.) was added purified water (8.94 kg, 2 vol.). To this mixture was slowly added concentrated HC1 (3.10 kg, 3.5 eq.) while maintaining the temperature below about 35 °C. The mixture was stirred at 30 ± 5 °C for about 1.5 h and HPLC analysis indicated the presence the compound of Formula (I) in 99.8% (AUC) purity with respect to compound 10.
[00593] Then, the compound of Formula (I) mixture was cooled to 25 ± 5 °C. The pH of the mixture was adjusted to about 8 using pre filtered ammonium hydroxide (1.90 kg). After stirring for about 15 min, Form C crystal seeds (13.88 g) were added. After stirring for about 15 min, purified water (58.0 kg, 13 vol.) was charged over a period of about 2 h. After stirring the mixture for 15 h at 25 ± 5 °C, the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper. The filter cake was rinsed with purified water (18.55 kg, 4 vol.) followed by pre -filtered n-heptane (6.10 kg, 2 vol.). After conditioning the filter cake for about 24 h, HPLC analysis of the filter cake indicated the presence the compound of Formula (I) in about 99.2% (AUC) purity.
[00594] To the filter cake was added dichloromethane (29.9 kg, 5 vol.) and the slurry was stirred at 25 ± 5 °C for about 24 h. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with DCM (6.10 kg, 1 vol.). After conditioning the filter cake for about 22 h, the filter cake was dried for about 2 days in vacuo at 50 ± 5 °C to afford the compound of Formula (I) in 99.6% (AUC) purity. The compound of Formula (I) was consistent with a Form A reference by XRPD.
[00595] To this solid was added purified water (44.6 kg, 10 vol.) and pre filtered 2-propanol (3.0 kg, 0.8 vol.). After stirring for about 6 h, a sample of the solids in the slurry was analyzed by XRPD and was consistent with a Form C reference. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with purified water (22.35 kg, 5 vol.) followed by pre filtered n-heptane (9.15 kg, 3 vol.). After conditioning the filter cake for about 18 h, the filter cake was dried in vacuo for about 5 days at 50 ± 5 °C.
[00596] This process afforded a compound of Formula (I) in about 99.6% (AUC) purity, and a chiral purity of greater than about 99% (AUC). An XRPD of the solid was consistent with a Form C reference standard. :H NMR (DMSO-<i6) and IR of the product conformed with reference standard.
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http://www.google.com/patents/US20140120083
In some embodiments, the compound has the following structure:
which is also referred to herein as Compound 292.
In some embodiments, a polymorph of a compound disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2012-0184568 (“the ‘568 publication”), which is hereby incorporated by reference in its entirety.
In one embodiment, the compound is Form A of Compound 292, as described in the ‘568 publication. In another embodiment, the compound is Form B of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form C of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form D of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form E of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form F of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form G of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form H of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form I of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form J of Compound 292, as described in the ‘568 publication.
In specific embodiments, provided herein is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application. In specific embodiments, provided herein is a pharmaceutically acceptable form of Compound 292, which is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application.
Any of the compounds (PI3K modulators) disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, isotopically labeled derivatives, or mixtures thereof.
Chemical entities described herein can be synthesized according to exemplary methods disclosed in U.S. Patent Publication No. US 2009/0312319, International Patent Publication No. WO 2011/008302A1, and U.S. Patent Publication No. 2012-0184568, each of which is hereby incorporated by reference in its entirety, and/or according to methods known in the art.
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KEY Duvelisib, IPI-145, INK-1197, AbbVie, INFINITY, chronic lymphocytic leukemia, phase 3, orphan drug
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