WO2016145286A1 - Synthesis of cyclocreatine and analogs thereof - Google Patents
Synthesis of cyclocreatine and analogs thereof Download PDFInfo
- Publication number
- WO2016145286A1 WO2016145286A1 PCT/US2016/021947 US2016021947W WO2016145286A1 WO 2016145286 A1 WO2016145286 A1 WO 2016145286A1 US 2016021947 W US2016021947 W US 2016021947W WO 2016145286 A1 WO2016145286 A1 WO 2016145286A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- cyclocreatine
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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- 0 CC(C)(CN1*)C(*)(*)NC1=N Chemical compound CC(C)(CN1*)C(*)(*)NC1=N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/12—Nitrogen atoms not forming part of a nitro radical
- C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/02—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of guanidine from cyanamide, calcium cyanamide or dicyandiamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
Definitions
- the invention relates to a chemical process and intermediates for the preparation of cyclocreatine and related cyclic creatine analogs with application in the treatment of creatine transporter deficiency.
- Cyclocreatine ((2-iminoimidazolidin-l-yl)acetic acid ) is used in the treatment of creatine transporter defect.
- a mutation affects the creatine transporter thereby preventing creatine from crossing the blood-brain barrier (BBB), leading to a deficiency of this important amino acid in the brain.
- Creatine is a polar small molecule and requires active transport to cross the BBB.
- cyclocreatine is more lipophilic owing to its two additional methylene groups and is able to cross the BBB by passive diffusion, thereby functioning as a creatine surrogate.
- cyanogen bromide a highly toxic and reactive compound
- the present invention is directed to a process for the preparation of a compound of formula (I):
- Y is CH 2 C0 2 H, CH 2 CO RiR 2 or CH 2 C0 2 Ri;
- Ri, R 2 independently of each other, is hydrogen, lower alkyl, C 7 -C 12 alkyl or lower cycloalkyl;
- n 1, 2, 3, 4 or 5.
- the present invention is directed at an improved synthetic method for making
- Cyanamide is a readily available commodity chemical and is significantly less toxic than cyanogen bromide.
- Lower alkyl or "Ci-C 6 alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms.
- Examples of a lower alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.
- C7-C 12 alkyl refers to a straight or branched chain saturated hydrocarbon containing 7- 12 carbon atoms.
- cycloalkyl refers to a cyclic hydrocarbon containing 3-6 carbon atoms.
- cycloalkyl group examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- substitutable hydrogens on a lower alkyl, C7-C12 alkyl or cycloalkyl can be substituted independently with one or more substituents, for example 1, 2 or 3 substituents.
- substituents include, but are not limited to, halogen, C1-C3 alkyl, hydroxyl, alkoxy, oxo and cyano groups.
- a "patient” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus monkey, and the terms “patient” and “subject” are used interchangeably herein.
- Representative "pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 -di sulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
- water-soluble and water-insoluble salts such as the acetate, amsonate (4,4-diaminostilbene-2, 2 -di sulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bro
- a "therapeutically effective amount" when used in connection with cyclocreatine is an amount effective for treating or preventing a cyclocreatine-regulated disease or disorder.
- the present invention describes a method for the preparation of various cyclic analogs of creatine (2) by the condensation of diamines or their salts (1) with cyanamide in a suitable solvent to afford 7 and ammonia or a salt thereof.
- the diamine may be a purified substance or a mixture containing approximately 20-99% 6.
- the product 2 may, in some embodiments, be further purified by crystallization or slurry from water or another suitable solvent to afford 7 in > 97% chemical purity.
- Alternate embodiments of 2 can include compounds of formula:
- Ri, R 2 , R 3 , R4, independently of each other, can be hydrogen, lower alkyl or cycloalkyl, or a pharmaceutically acceptable salt thereof.
- a process for the preparation of a compound of formula (I): or a pharmaceutically acceptable salt thereof comprising the step of reacting a compound of formula (II):
- Y is CH2CO2H, CH2CO R1R2 or CH2CO2R1;
- Ri, R 2 independently of each other, is hydrogen, lower alkyl, C7-C 12 alkyl or lower cycloalkyl;
- n 1, 2, 3, 4 or 5.
- n 1
- a process for the preparation of a compound of formula (I), wherein n 1
- a process for the preparation of a compound of formula (I), wherein the compound of formula (I) is cyclocreatine or a pharmaceutically acceptable salt thereof.
- Y is CH 2 C0 2 H, CH 2 CO RiR 2 or CH 2 C0 2 Ri;
- Ri, R 2 , R 3 , R4, independently of each other, is hydrogen, lower alkyl, C 7 -Ci 2 alkyl or cycloalkyl, or a pharmaceutically acceptable salt thereof.
- Intermediate A can be formed by the following process: Chloroacetic acid (3) can be reacted with ten molar equivalents of ethyl enediame (4) in DMSO at 5-10°C for 7.5 h and the reaction mixture can be distilled under reduced pressure to remove most of the ethylene diamine. The resultant crude residue can be treated with DMSO and filtered to afford crude [(2- Aminoethyl)amino]acetic acid (3). This can be washed with isopropanol and MTBE and dried under vacuum to produce 3 in 88% isolated yield. Product 3 can then be reacted in water by addition of an aqueous solution of cyanamide (one molar equivalent) and heating from 22°C to 84°C.
- the resultant cyclocreatine solid that forms in solution can be filtered and subsequently slurried in water at ambient temperature.
- the cyclocreatine was filtered and dried under vacuum with an isolated yield of 43%.
- Intermediate A is a chemical composition that forms during the preparation of cyclocreatine from 3 and cyanamide. This intermediate can further react to form cyclocreatine.
- Intermediate A, as well as isomeric form B, can be useful in the preparation of cyclocreatine such that a solution of either intermediate may react in a suitable solvent, such as water, to form cyclocreatine at room temperature or elevated temperatures such as 40-80°C.
- cyclocreatine or a pharmaceutically acceptable salt thereof, prepared by a process comprising the step of reacting a compound of formula (A):
- a 40 mL vial with a stopper and magnetic stir bar was charged with ethylenediamine (9.2 g, 153.7 mmol).
- a syringe pump was charged with a solution of chloroacetic acid (0.968 g, 10.24 mmol) in PhMe (total volume 9.5 mL). The syringe pump was set to deliver at a rate of 19.0 mL/h.
- the vial containing the ethylenediamine was heated in an aluminum heating block to 70°C and the addition initiated at this time. After the addition was complete ( ⁇ 30 min), the vial was removed from the heating block and cooled to room temperature. The supernatant layer of liquid was removed by pipette and the remainder evaporated under high vacuum. HPLC/MS analysis of the residue revealed 92.8% mono-acid 3 and 7.2% diacid.
- EDA ethylenediamine
- the syringe was placed onto a syringe pump set to deliver 3.3 mL/h (total addition time was 8 h).
- the syringe needle was inserted into the flask via the septum and placed below the level of EDA. Addition occurred at ambient temperature.
- reaction mixture was stirred for lOh at ambient temperature.
- the reaction mixture was concentrated (60 °C, -10 mbar) to 47 g.
- Toluene (50 mL) was added and the mixture was concentrated in order to azeotrope EDA. More toluene (50 mL) was added and the mixture was concentrated to 41 g. DMSO (30 mL) was added and the mixture was cooled in an ice/water bath for 30 min. The cooling bath was removed and the mixture was stirred at ambient temperature for 30 min. The mixture was filtered.
- a solution of chloroacetic acid (1 equivalent) in DMSO is added to propane- 1,3 -diamine (10 equivalents) over a period of 8 hours.
- the reaction mixture is concentrated by vacuum distillation and DMSO is added.
- the mixture is cooled to 0 °C, and then warmed back up to ambient temperature.
- the resulting slurry is filtered, and the flask and solids are washed sequentially with DMSO, isopropanol, and t-butylmethyl ether.
- the solids are dried and dissolved into water.
- Cyanamide 50 wt% solution in water, 1 equivalent
- the reaction is cooled to 0 °C and the resulting slurry is filtered.
- the flask and solids are washed with water and dried to give 4.
- a solution of chloroacetic acid was prepared by dissolving chloroacetic acid (500.0 g, 5.29 mol) in DMSO (515.6 g).
- DMSO DMSO
- a 5 L flask, fitted with nitrogen inlet, mechanical stirrer, thermocouple, and peristaltic metering pump was charged with ethylenediamine (3537 mL, 52.9 mol). Cooling with ice water was initiated. The solution in DMSO was then added via a metering pump.
- Table 1 shows the reaction conditions during addition of chloracetic acid solution to ethylenediamine:
- the reaction mixture was concentrated by rotary evaporation (50-60°C, 14-21 Torr) to remove ethylenediamine. Total amount of distillate collected was 2400 mL. Toluene (900 mL) was added to the residue and the mixture was concentrated by rotary evaporation (60°C, 30 Torr). The residue was transferred to a 5 L flask using DMSO (3 kg). The internal temperature was 28°C and the mixture appeared cloudy. Cooling (ice/water) was initiated. The reaction mixture was stirred overnight. The resulting suspension was filtered through filter paper. The flask and solids were washed with DMSO (2 x 500 mL).
- HPLC/MS showed consumption of 3. Heat was shut off and the reaction was cooled in an ice/water bath. The mixture was then stirred overnight and filtered through filter paper. The flask and solids were washed with deionized water (150 mL). The wet solids were transferred to a 2 L flask, equipped with a mechanical stirrer. Deionized water (450 mL) was added and the thick slurry was stirred at ambient temperature for 3 h. The mixture was filtered through filter paper and the flask and solids were washed with IPA (450 mL).
- a 100 mL round bottom flask, equipped with nitrogen inlet, magnetic stirrer and thermocouple is charged with compound 3 (4.8 g, 4.05 mmol, 1.00 equiv) and deionized water (500 mL).
- the resulting slurry is stirred at ambient temperature (22°C) for three days.
- Y is CH 2 C0 2 H, CH 2 CO RiR 2 or CH 2 C0 2 Ri;
- Ri, R 2 independently of each other, is hydrogen, lower alkyl, C 7 -C 12 alkyl or lower cycloalkyl;
- n 1, 2, 3, 4 or 5.
- Y is CH 2 C0 2 H, CH 2 CO RiR 2 or CH 2 C0 2 Ri;
- Ri, R 2 , R 3 , R 4 independently of each other, is hydrogen, lower alkyl, C 7 -C 12 alkyl or cycloalkyl, or a pharmaceutically acceptable salt thereof. 6.
- a process for making cyclocreatine or a pharmaceutically acceptable salt thereof comprising the step of reacting a compound of formula (B):
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Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017547543A JP2018513122A (en) | 2015-03-11 | 2016-03-11 | Synthesis of cyclocreatine and its analogues |
CA2979224A CA2979224A1 (en) | 2015-03-11 | 2016-03-11 | Synthesis of cyclocreatine and analogs thereof |
AU2016228785A AU2016228785A1 (en) | 2015-03-11 | 2016-03-11 | Synthesis of cyclocreatine and analogs thereof |
EP16762577.1A EP3267795A4 (en) | 2015-03-11 | 2016-03-11 | Synthesis of cyclocreatine and analogs thereof |
US15/556,657 US10081605B2 (en) | 2015-03-11 | 2016-03-11 | Synthesis of cyclocreatine and analogs thereof |
CN201680025144.XA CN107529753A (en) | 2015-03-11 | 2016-03-11 | The synthesis of circular muscle acid and the like |
HK18104657.6A HK1245015A1 (en) | 2015-03-11 | 2018-04-10 | Synthesis of cyclocreatine and analogs thereof |
US16/107,103 US10377721B2 (en) | 2015-03-11 | 2018-08-21 | Synthesis of cyclocreatine and analogs thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US201562131321P | 2015-03-11 | 2015-03-11 | |
US62/131,321 | 2015-03-11 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US15/556,657 A-371-Of-International US10081605B2 (en) | 2015-03-11 | 2016-03-11 | Synthesis of cyclocreatine and analogs thereof |
US16/107,103 Division US10377721B2 (en) | 2015-03-11 | 2018-08-21 | Synthesis of cyclocreatine and analogs thereof |
Publications (1)
Publication Number | Publication Date |
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WO2016145286A1 true WO2016145286A1 (en) | 2016-09-15 |
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Family Applications (1)
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PCT/US2016/021947 WO2016145286A1 (en) | 2015-03-11 | 2016-03-11 | Synthesis of cyclocreatine and analogs thereof |
Country Status (8)
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US (2) | US10081605B2 (en) |
EP (1) | EP3267795A4 (en) |
JP (1) | JP2018513122A (en) |
CN (1) | CN107529753A (en) |
AU (1) | AU2016228785A1 (en) |
CA (1) | CA2979224A1 (en) |
HK (1) | HK1245015A1 (en) |
WO (1) | WO2016145286A1 (en) |
Families Citing this family (1)
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WO2020123581A1 (en) | 2018-12-11 | 2020-06-18 | Sirrus, Inc. | Emulsion polymers of 1,1-dicarbonyl 1-alkenes of controlled particle size |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5321030A (en) | 1989-02-14 | 1994-06-14 | Amira, Inc. | Creatine analogs having antiviral activity |
WO2006073923A2 (en) | 2004-12-30 | 2006-07-13 | Nour Heart, Inc. | Phosphagen synthesis |
US7834144B2 (en) * | 2005-09-09 | 2010-11-16 | Novartis Ag | Prion-specific peptoid reagents |
WO2014204763A1 (en) * | 2013-06-17 | 2014-12-24 | 3M Innovative Properties Company | Process for preparing guanidino-functional monomers |
WO2016036699A1 (en) | 2014-09-03 | 2016-03-10 | Lumos Pharma, Inc. | Synthesis of cyclocreatine and analogs thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69535104T2 (en) * | 1994-11-08 | 2007-02-08 | Avicena Group, Inc., Cambridge | USE OF CREATINE OR CREATINANOLOGISTS FOR THE TREATMENT OF HUNTINGTON CHOREA, MORBUS PARKINSON AND AMYOTROPHES LATERAL SCLEROSIS |
ES2306924T3 (en) * | 2003-05-02 | 2008-11-16 | Polyphor Ag | PEPTIDOMIMETICS FIXED TO A MATRIX AS MEDICATIONS AGAINST HIV AND CANCER. |
CN103923014A (en) * | 2014-05-05 | 2014-07-16 | 宁夏宝马药业有限公司 | Preparation method of cyclocreatine |
-
2016
- 2016-03-11 EP EP16762577.1A patent/EP3267795A4/en not_active Withdrawn
- 2016-03-11 US US15/556,657 patent/US10081605B2/en not_active Expired - Fee Related
- 2016-03-11 JP JP2017547543A patent/JP2018513122A/en active Pending
- 2016-03-11 CA CA2979224A patent/CA2979224A1/en not_active Abandoned
- 2016-03-11 AU AU2016228785A patent/AU2016228785A1/en not_active Abandoned
- 2016-03-11 CN CN201680025144.XA patent/CN107529753A/en active Pending
- 2016-03-11 WO PCT/US2016/021947 patent/WO2016145286A1/en active Application Filing
-
2018
- 2018-04-10 HK HK18104657.6A patent/HK1245015A1/en unknown
- 2018-08-21 US US16/107,103 patent/US10377721B2/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5321030A (en) | 1989-02-14 | 1994-06-14 | Amira, Inc. | Creatine analogs having antiviral activity |
WO2006073923A2 (en) | 2004-12-30 | 2006-07-13 | Nour Heart, Inc. | Phosphagen synthesis |
US7834144B2 (en) * | 2005-09-09 | 2010-11-16 | Novartis Ag | Prion-specific peptoid reagents |
WO2014204763A1 (en) * | 2013-06-17 | 2014-12-24 | 3M Innovative Properties Company | Process for preparing guanidino-functional monomers |
WO2016036699A1 (en) | 2014-09-03 | 2016-03-10 | Lumos Pharma, Inc. | Synthesis of cyclocreatine and analogs thereof |
Non-Patent Citations (3)
Title |
---|
ROWLEY, G. L.GREENLEAF, A. L.KENYON, G. L., J. AM. CHEM. SOC., vol. 93, 1971, pages 5542 - 5551 |
ROWLEY, GL ET AL.: "On the Specificity of Creatine Kinase. New Glycocyamines and Glycocyamine Analogs Related to Creatine.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 93, no. 21, 20 October 1971 (1971-10-20), pages 5542 - 5551, XP055196662 * |
See also references of EP3267795A4 * |
Also Published As
Publication number | Publication date |
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EP3267795A4 (en) | 2018-11-21 |
JP2018513122A (en) | 2018-05-24 |
US20180044299A1 (en) | 2018-02-15 |
AU2016228785A1 (en) | 2017-09-28 |
US10377721B2 (en) | 2019-08-13 |
CA2979224A1 (en) | 2016-09-15 |
CN107529753A (en) | 2018-01-02 |
US10081605B2 (en) | 2018-09-25 |
US20180354910A1 (en) | 2018-12-13 |
HK1245015A1 (en) | 2018-08-24 |
EP3267795A1 (en) | 2018-01-17 |
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