Crinecerfont

Crinecerfont

CAS 752253-39-7

SSR125543

SSR 125543

SSR-125543, WHO 10958, UNII-MFT24BX55I, 06-RORI,NBI-74788

• (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine
• 2-Thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-((1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-2-propynyl-
• 2-Thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl

FDA APPROVED 12/13/2024, Crenessity, To treat classic congenital adrenal hyperplasia 
Press Release

4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine

WeightAverage: 483.04
Monoisotopic: 482.1594906

Chemical FormulaC₂₇H₂₈ClFN₂OS

CAS No. : 321839-75-2

Crinecerfont, sold under the brand name Crenessity, is a medication used for the treatment of congenital adrenal hyperplasia.^[1] It is a corticotropin-releasing factor type 1 receptor (CRF1R) antagonist developed to treat classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD).^[1] It is taken by mouth.^[1]

The most common side effects of crinecerfont in adults include fatigue, dizziness, and arthralgia (joint pain).^[2] For children, the most common side effects include headache, abdominal pain, and fatigue.^[2]

Crinecerfont was approved for medical use in the United States in December 2024.^[2][3] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[4]

A medication used to reduce the amount of steroid replacement required in patients with a genetic disease that causes, amongst other symptoms, a steroid deficiency.

• OriginatorSanofi
• DeveloperNeurocrine Biosciences; Sanofi
• ClassAmines; Antidepressants; Anxiolytics; Chlorobenzenes; Cyclopropanes; Fluorobenzenes; Halogenated hydrocarbons; Phenyl ethers; Small molecules; Thiazines; Thiazoles
• Mechanism of ActionCorticotropin releasing factor receptor 1 antagonists

• Orphan Drug StatusYes – Congenital adrenal hyperplasia

• MarketedCongenital adrenal hyperplasia
• DiscontinuedMajor depressive disorder; Post-traumatic stress disorders

20 Dec 2024Launched for Congenital adrenal hyperplasia (Adjunctive treatment, In adolescents, In children) in USA (PO)

• 20 Dec 2024Launched for Congenital adrenal hyperplasia (Adjunctive treatment, In adolescents, In children, In the elderly, In adults) in USA (PO)
• 20 Dec 2024Launched for Congenital adrenal hyperplasia (Adjunctive treatment, In the elderly, In adults) in USA (PO)

SYN

https://patents.google.com/patent/US12128033

Example processes and certain intermediates of the present invention are shown in Scheme I to Scheme VII below.

A representative Coupling-Step of 2-cyclopropylacetic acid (Compound

 1A) with N,O-dimethylhydroxylamine or a salt thereof in the presence of a coupling-step reagent (e.g., 1,1′-carbonyldiimidazole), a coupling-step base (e.g., triethylamine), and a coupling-step solvent (e.g., dichloromethane) to prepare 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound

 2A) is provided below in Scheme I.

A representative Reacting-Step between 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound

 2A) with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting-step solvent (e.g., tetrahydrofuran (THF)) to prepare 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound

 3A) is provided below in Scheme II.

A representative Condensing-Step of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound

 3A) with a Compound of Formula (Ic) or a salt thereof, in the presence of a condensing-step acid (e.g., p-toluenesulfonic acid) and a condensing-step solvent (e.g., toluene) to prepare a Compound of Formula (Ie) is provided below in Scheme III.

• • wherein:
  • R^1c, R^2c, and R^3c are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

A representative Reducing-Step of a Compound of Formula (Ie) in the presence of a reducing-catalyst (e.g., sponge nickel and Pd/Cu—C), hydrogen, and a reducing-step solvent (e.g., ethanol) to prepare a Compound of Formula (Ig) is provided below in Scheme IV.

• • wherein:
  • R^1c, R^2c, and R^3c are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

A representative Deprotecting-Step of a Compound of Formula (Ig), or a salt thereof, in the presence of a deprotecting-catalyst (e.g., Pd), hydrogen, and a deprotecting-step solvent (e.g., ethanol) to prepare (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound

 6A) or a salt thereof is provided below in Scheme V.

• • wherein:
  • R^1c, R^2c, and R^3c are each independently selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and halogen.

A representative Cyclizing-Step of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound

 6A) or a salt thereof, with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound

 8A) or a tautomeric form thereof, in the presence of a cyclizing-step solvent (e.g., n-heptane) to prepare (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound

 9A) or a salt thereof is provided below in Scheme VI.

A representative Alkylating-Step of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound

 9A) or a salt thereof, with a Compound of Formula (Ii), wherein LG is suitable leaving group (e.g., Br), in the presence of an alkylating-step solvent (e.g., methyl tert-butyl ether (MTBE), toluene, and mixtures thereof), a phase-transfer catalyst (e.g., tetra-n-butylammonium bromide (TBAB)), an alkylating-step base (e.g., potassium hydroxide), and water to prepare 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof is provided below in Scheme VII.

One aspect of the present invention includes every combination of one or more process steps and intermediates related thereto used in the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), and/or pharmaceutically acceptable salts, and crystalline forms thereof, such as those processes exemplified by Schemes I, II, III, IV, V, VI, VII, and VII (supra) and Compounds contained therein.

Compound

 8A was previously described in International Publication Number WO2010/125414 by Sanofi-Aventis.Example 1: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), See FIG. 5 for a general synthetic schemeStep1A: Preparation of 2-Cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A)

A suspension of 1,1′-carbonyldiimidazole (CDI, 152.6 kg, 1.01 eq.) in DCM (682 kg, 513 L, 7.3 w/w relative to 2-cyclopropylacetic acid) was treated with a solution of 2-cyclopropylacetic acid (Compound

 1A, 93.6 kg, 1 eq.) in DCM (248 kg, 186 L, 2.65 w/w) over at least 1 h, keeping the temperature ≤25° C. and compensating for significant effervescence. The resulting mixture was stirred for 15 min at 22° C. and then N,O-dimethylhydroxylamine-HCl (93.6 kg, 1.03 eq.) was added in portions, keeping the temperature ≤30° C. Subsequently, triethylamine (46.4 kg, 0.49 eq.) was added to the stirring mixture at 20-25° C. The resulting mixture was stirred at 22° C. at least 1 h. The mixture was washed once with KHSO₄ solution (0.24 M, 357.1 kg, 0.09 eq.), once with KHSO₄ solution (0.40 M, 365.4 kg, 0.15 eq.), once with KHSO₄ solution (0.80 M, 384.5 kg, 0.30 eq.), and once with NaHCO₃ solution (0.60 M, 393.1 kg, 0.24 eq.). Residual DCM was removed by two put-and-takes of THF (166.6 kg, 1.78 w/w) and vacuum distillation (50-60° C., to minimum volume/until distillation stops) to provide Compound

 2A. THF (333.2 kg. 3.56 w/w) was added and the yield was determined by correcting for the LOD and GC-FID purity of the sample (131.5 kg, 98.2% corrected). ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm) −0.01-0.03 (m, 2H), 0.32-0.36 (m, 2H), 0.81-0.90 (br m, 1H), 2.18 (d, J=6.80 Hz, 2H), 2.97 (s, 3H), 3.53 (s, 3H). ESI-MS: 144.0 [M+H]⁺.Step 1B: Preparation of 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A)

Mg (turnings, 28.6 kg, 1.37 eq.) were suspended in THF (244.7 kg, 2.0 w/w) and DIBAL-H (1 M in n-heptane, 18.9 kg, 0.03 eq.) was added dropwise at 30° C. The resulting mixture was stirred at 30° C. for at least 10 min and then 4-bromo-2-fluoro-1-methylbenzene (neat, 21.1 kg, 0.13 eq.) was added over at least 30 min at 30-50° C. Subsequently, the mixture was treated with a solution of 4-bromo-2-fluoro-1-methylbenzene (191.6 kg, 1.18 eq.) in THF (414.5 kg, 3.37 w/w) at 30-50° C. over 3 h or less. The mixture was stirred at 30° C. for at least 1 h. The mixture was cooled to 12-18° C. and subsequently treated with 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound

 2A, 123.0 kg, 1 eq., 25.9% w/w solution in THF) over at least 1 h at 15-25° C. The resulting mixture was stirred at 20-25° C. for at least 1 h. The stirring mixture was then treated with aqueous HCl (3 M, 10.3% w/w, 668.9 kg, 2.24 eq.) at 10-25° C. and the resulting mixture was stirred at least 2 h until no Mg turnings were observed (check pH 3.0-3.5). The layers were separated, and the aqueous layer discarded. The organic layer was distilled at 55-65° C. and 400 mbar until distillation halts. Heptane (290.3 kg, 2.36 w/w) was added. The layers were separated, and the organic layer was washed once with NaHCO₃ solution (0.63 M, 211.6 kg, 0.15 eq.) and once with NaCl solution (2.57 M, 213.0 kg, 0.55 eq.). The residual solvents were removed by vacuum distillation at 58-62° C. until distillation stops and then one put-and-take of toluene (275.5 kg, 2.24 w/w) at 107-117° C. until distillation stops. Toluene (275.5 kg, 2.24 w/w) was added and the yield was determined by correcting for the LOD and GC-FID purity of the sample (150.7 kg, 91.3% corrected). ¹H NMR (400 MHz, DMSO-d₆) β (ppm) 0.07-0.21 (m, 2H), 0.40-0.54 (m, 2H), 1.02 (ttt, J=8.16, 8.16, 6.68, 6.68, 4.86, 4.86 Hz, 1H), 2.30 (d, J=1.77 Hz, 3H), 2.91 (d, J=6.57 Hz, 2H), 7.44 (t, J=7.83 Hz, 1H), 7.57-7.78 (m, 2H). ESI-MS: 193.1 [M+H]⁺.Step 1C: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine (Compound 4A)

A mixture of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound

 3A, 150.7 kg, 1 eq., as a 27.6% w/w solution in toluene), (S)-(−)-1-phenylethylamine (112.9 kg, 1.19 eq.), and p-toluenesulfonic acid (7.4 kg, 0.05 eq.) was heated to reflux at 110-120° C. for 23-25 h in a reactor set up in a Dean-Stark configuration. The solvent was then removed at 125-135° C. under atmospheric pressure until distillation halts and a portion of toluene (275 kg, 2.24 w/w) was added to afford a suspension. The suspension was heated to reflux at 110-120° C. for 23-25 h. The mixture was cooled to 22° C. and washed twice with aqueous NH₄Cl (10%, 301.2 kg, 0.72 eq.) and once with aqueous NaHCO₃ (5%, 301.2 kg, 0.23 eq., check pH 8-9). The solvent was removed at 125-135° C. and atmospheric pressure to a target volume of 256 L, the mixture was filtered over CELITE®, and the cake was washed with toluene (25 kg). The resulting mixture containing Compound 4A was used directly in the next step without further isolation. The yield was determined by correcting for the LOD and GC-FID purity of the sample (208.4 kg, 90.0% corrected). EL-MS: 294.1 [M−H]*, 190.1 [M-C₆H₅CH(CH₃)]+, 105.1 [C₆H₅CH(CH₃)]+.Step 1D: Preparation of (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)-N—((S)-1-phenylethyl)ethan-1-amine (Compound 5A) as the Hydrochloride Salt

Sponge nickel catalyst (144 kg, 0.70 w/w, shipped as a 50% w/w suspension in water) was added to a hydrogenation reactor, equipped with a dip tube capable of removing material from the top of the mass inside, minimizing the amount of water introduced. The supernatant was discarded, ethanol (329.3 kg, 1.58 w/w, anhydrous) was added, the suspension was stirred and then allowed to settle. This process was repeated four more times and the supernatant is checked; ≤1% H₂O w/w (Karl Fisher (KF)). Compound 4A (208.4 kg, 1 eq., as a 62.6% solution in toluene) was added to the mixture in the hydrogenation reactor. Ethanol (389.4 kg, 1.86 w/w) was used to rinse the addition flask into the hydrogenation reactor. The hydrogenation reactor was pressurized/depressurized twice with nitrogen (2 bar), twice with hydrogen (5 bar), and then pressurized with hydrogen (9.8-10.2 bar). The resulting mixture was heated to 33-37° C. and stirred for 17-19 h. The system was depressurized/pressurized three times with nitrogen (1 bar). The suspension was filtered and washed three times with ethanol (total amount, 493.8 kg, 2.37 w/w). The filtrate was combined with HCl (concentrated, 83.4 kg, 1.07 eq.) and the resulting mixture stirred 25-35 min at 20-24° C. The mixture was concentrated by distillation at 78-80° C. and atmospheric pressure to remove water with a distillate target volume of 1167 L (5.6 L/kg based on imine Compound 4A) and the KF of the solution checked (≤1.5% H₂O w/w). The mixture was stirred at 48-52° C. for 55-65 min, then 68-72° C. for 55-65 min, then cooled to 20-24° C. at a rate of 12° C./h and stirred for 25-35 min, then cooled to 0-4° C. at a rate of 10° C./h and stirred for 55-65 min. The suspension was filtered, the cake was washed twice with precooled ethanol (total amount, 329.2 kg, 1.58 w/w, 0° C.), and the collected solid was dried at 40° C. to afford Compound

 5A as the HCl salt (156.5 kg, 66.4% uncorrected). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) −0.33–0.06 (m, 2H), 0.11-0.31 (m, 3H), 1.57 (d, J=6.57 Hz, 3H), 1.95 (br t, J=7.07 Hz, 2H), 2.26 (d, J=1.26 Hz, 3H), 3.68 (br d, J=7.83 Hz, 1H), 3.92 (br t, J=6.44 Hz, 1H), 6.98 (dd, J=7.71, 1.14 Hz, 1H), 7.28-7.36 (m, 2H), 7.37-7.50 (m, 5H). EST-MS: 298.2 m/z [M+H]+.Step 1E: Preparation of (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) as the Hydrochloride Salt

Compound

 5A (HCl salt, 156.5 kg, 1.00 eq.) and Pd/C (7.8 kg, 10% Pd basis) were added to an inerted hydrogenation reactor. The reactor was then pressurized/depressurized twice with nitrogen (2 bar) and then methanol (494.5 kg, 3.16 w/w) was added. The reactor was depressurized/pressurized three times with nitrogen (2 bar) then three times with hydrogen (5 bar), pressurized with hydrogen (9.8-10.2 bar), heated to 58-62° C. and stirred for 7-9 h. The reaction mixture was cooled to 20-24° C. The reactor was depressurized/pressurized three times with nitrogen (1 bar) and the suspension was filtered and washed three times with methanol (total amount, 492.9 kg, 3.15 w/w). The solution was concentrated at 63-67° C. and atmospheric pressure to a distillate target volume of 1408 L (9.0 L/kg Compound

 6A), n-Heptane (1173.8 kg, 7.5 w/w) was added and the resulting mixture was heated to reflux at 65-80° C. and atmospheric pressure in Dean-Stark configuration to remove methanol. The suspension was cooled to 31-35° C. and filtered, the cake washed with n-heptane (147.1 kg, 0.94 w/w), and the solid dried at 40° C. to provide Compound

 6A as the HCl salt (101.0 kg, 93.8% uncorrected, 99.6% ee). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) −0.12-0.14 (m, 2H), 0.26-0.42 (m, 2H), 0.44-0.55 (m, 1H), 1.70-1.83 (m, 2H), 2.23 (d, J=1.52 Hz, 3H), 4.24 (t, J=7.33 Hz, 1H), 7.22-7.29 (m, 1H), 7.29-7.36 (m, 1H), 7.40 (dd, J=10.99, 1.39 Hz, 1H). ESI-MS: 194.2 [M+H]⁺, 177.0 [M-NH₂]⁺.Step 1F: Preparation of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A)

A mixture of n-heptane (146 kg), water (142 kg), Compound

 6A (HCl salt, 57.4 kg), and aqueous sodium hydroxide (30% w/w, 41.0 kg) was stirred together. The layers were partitioned, and the aqueous layer removed. The organic layer was washed with water (170 kg) and the layers partitioned. The organic layer was set aside, n-Heptane (145 kg) and 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound

 8A, 66.1 kg, the preparation of Compound

 8A has been previously described in International Publication Number WO2010/125414) were added to the reactor and heated to 85° C. The previously set aside organic layer containing the free base of Compound

 6A was added at 84-85° C. to the reactor and rinsed with n-heptane (20 kg). The resulting mixture was stirred for 2 h at 83° C. Subsequently, the solvent was switched to methanol by four put-and-take additions/vacuum distillations of methanol (180 kg) at 55° C. with the target volume being 287 L remaining in the reactor. The suspension was cooled to 5° C. and water (570 kg) was added over 4 h at 5-10° C., with the first 60 kg added very slowly. The suspension was aged 2 h at 5° C. and then isolated by filtration, washed with a mixture of methanol/water (91/115 kg) and then a mixture of methanol/water (134/57 kg). The yellow solid was dried at 25° C. and 1 mbar for 17 h then 40° C. and 1 mbar for 22 h to afford Compound

 9A (97.4 kg, 87.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm −0.01-0.14 (m, 2H), 0.29-0.42 (m, 2H), 0.61-0.73 (m, 1H), 1.47 (dt, J=13.83, 6.85 Hz, 1H), 1.76 (dt, J=13.89, 7.20 Hz, 1H), 2.00 (s, 3H), 2.11 (s, 3H), 2.19 (d, J=1.01 Hz, 3H), 3.82 (s, 3H), 4.54 (q, J=7.58 Hz, 1H), 7.00 (s, 1H), 7.06 (d, J=0.76 Hz, 1H), 7.08-7.14 (m, 2H), 7.18-7.23 (m, 1H), 7.89 (d, 1=8.08 Hz, 1H). ESI-MS: 445.3 m/z [M+H]⁺.Step 1G: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (279 kg), tetra-n-butylammonium bromide (10.5 kg), and Compound

 9A (95.4 kg) were heated at 60° C. external temperature for 30 min and then cooled to 0° C. Aqueous potassium hydroxide (52.4% w/w, 364 kg) and propargyl bromide (39.4 kg as an 80% w/w solution in toluene, 1.19 eq.) were added at 0-5° C. The propargyl bromide additional funnel was washed with MTBE (25 kg) and the biphasic mixture was aged 14.5 h at 4-6° C. with vigorous stirring. Subsequently, water (191 kg) was added and the aqueous layer was discharged at 20° C. The organic layer was washed twice with water (382 kg) and once with aqueous acetic acid (5.26% w/w, 190 kg) at 20° C. The mixture is polish filtered, rinsed with ethanol (11 kg) and then the solvent switched to ethanol by 3 put-and-take additions/vacuum distillations of ethanol (300 kg) at 25-30° C. for the first cycle and then 35-40° C. with the target volume of each cycle being 250 L remaining in the reactor. Ethanol (164 kg) was added and the mixture heated at 60° C. external for 0.5 h before it was cooled to 25° C. in 1 h and seeded with authentic Form I (free base) of Compound 1 (0.340 kg) which can be prepared as described below in Example 2 and Example 3. The suspension was aged for 5 h, cooled to 0° C. in 2 h, aged 12 h, filtered, and washed twice with ethanol (24 kg each) pre-cooled to 0° C. The white solid was dried at 40° C. and 1 mbar for 19 h to yield 80.15 kg of Compound 1 (77.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 0.14 (qt, J=8.59, 4.42 Hz, 2H), 0.29-0.48 (m, 2H), 0.61-0.82 (m, 1H), 1.89 (dt, J=14.08, 6.98 Hz, 1H), 2.07 (br d, J=7.83 Hz, 1H), 2.10 (s, 3H), 2.14 (s, 3H), 2.20 (d, J=1.01 Hz, 3H), 3.11 (t, J=2.27 Hz, 1H), 3.83 (s, 3H), 3.94-4.22 (m, 2H), 5.26 (t, J=7.58 Hz, 1H), 7.05 (s, 1H), 7.10-7.36 (m, 4H). ESI-MS: 483.2 m/z [M+H]⁺.Example 2: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (2 mL), tetra-n-butylammonium bromide (110 mg), and Compound

 9A (1.003 g) at 0° C. was treated with aqueous potassium hydroxide (52.4% w/w, 1.80 mL, 2.73 g) and propargyl bromide (405 mg as an 80% w/w solution in toluene) maintaining the temperature at 0-5° C. The resulting biphasic mixture was aged 23 h at 4-6° C. Subsequently, water (2 mL) and MTBE (2 mL) were added and the aqueous layer was discharged. The organic layer was washed twice with water (4 mL) and once with aqueous acetic acid (5% w/w, 2 mL) at 20° C. Ethanol (4 mL) was added and then the solvent was switched to ethanol by 3 put-and-take additions/vacuum distillations of ethanol (6 mL) at 35-40° C. with the target volume of each cycle being 2 mL remaining in the vessel, except for the third cycle where the mixture was concentrated to dryness. Ethanol (4 mL) was added to the vessel and the mixture heated at 60° C. (external) for 0.5 h before it was cooled to 20° C. in 1 h and aged 18 h. The resulting suspension was cooled to 0° C., aged 6 h, filtered, and washed twice with ethanol (2 mL each) pre-cooled to 0° C. to afford a solid. The solid was dried at 40° C. under vacuum to afford Compound 1 (506 mg, 46% yield) as Form I. The ¹H NMR and ESI-MS data matches that as described above in Example 1, Step 1G.Example 3: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-1(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (40 mL), tetra-n-butylammonium bromide (1.1 g), and Compound

 9A (10.0 g) was heated to 45° C., aged for 10 min, then cooled to 0° C. The solution was treated with aqueous potassium hydroxide (52.4% w/w, 38.2 g) and propargyl bromide (3.36 g as an 80% w/w solution in toluene) maintaining the temperature at 0-5° C. The resulting biphasic mixture stirred vigorously for 16 h at 4-6° C. Subsequently, water (20 mL) was added and the aqueous layer was discharged. The organic layer was washed twice with water (40 mL) and once with aqueous acetic acid (5.2% w/w, 20 mL) at 20° C. The solvent was switched to ethanol by 4 put-and-take additions/vacuum distillations of ethanol (15 mL) at 35-40° C. with the target volume of each cycle being 15 mL remaining in the vessel. The solution was weighed to approximate the amount of ethanol remaining, and ethanol (26 mL) was added to the vessel to bring the total amount of ethanol to 40 mL. The solution was cooled to 4° C. and stirred for 45 min to afford a suspension. The suspension was heated to 38° C. in 15 min, aged 10 min, then cooled to 20° C. over 14 h. The suspension was cooled to 0° C., aged 1.5 h, filtered, and the solids washed twice with ethanol (7.5 mL each) pre-cooled to 0° C. The solid was dried at 40° C. under vacuum to afford Compound 1 (8.27 g, 76% yield) as Form I. The ¹H NMR and ESL-MS data matches that as described above in Example 1, Step 1G.

The crystalline free base Compound

 1, Form I was characterized by X-ray powder diffraction (XRPD) (FIG. 1

, Table 2) and DSC (FIG. 2

). The DSC indicated the crystalline Compound

 1, Form I has an onset of melt (temperature) at about 83.7° C. (76.6 J/g). The Thermogravimetric Analysis (TGA) (FIG. 2

) of the crystalline free base exhibited substantially no weight loss (about 0.2%) from room temperature to ˜125° C. indicating Form I for the free base of Compound

 1 is anhydrous.

Medical uses

Crinecerfont is indicated as adjunctive treatment to glucocorticoid replacement to control androgens in people four years of age and older with classic congenital adrenal hyperplasia.^[1][2]

Adverse effects

The US Food and Drug Administration prescription label for crinecerfont has a warning for acute adrenal insufficiency or adrenal crisis.^[2]

History

Crinecerfont’s approval is based on two randomized, double-blind, placebo-controlled trials in 182 adults and 103 children with classic congenital adrenal hyperplasia.^[2] In the first trial, 122 adults received crinecerfont twice daily and 60 received placebo twice daily for 24 weeks.^[2] After the first four weeks of the trial, the glucocorticoid dose was reduced to replacement levels, then adjusted based on levels of androstenedione, an androgen hormone.^[2] The primary measure of efficacy was the change from baseline in the total glucocorticoid daily dose while maintaining androstenedione control at the end of the trial.^[2] The group that received crinecerfont reduced their daily glucocorticoid dose by 27% while maintaining control of androstenedione levels, compared to a 10% daily glucocorticoid dose reduction in the group that received placebo.^[2]

In the second trial, 69 children received crinecerfont twice daily and 34 received placebo twice daily for 28 weeks.^[2] The primary measure of efficacy was the change from baseline in serum androstenedione at week four.^[2] The group that received crinecerfont experienced a statistically significant reduction from baseline in serum androstenedione, compared to an average increase from baseline in the placebo group.^[2] At the end of the trial, children assigned to crinecerfont were able to reduce their daily glucocorticoid dose by 18% while maintaining control of androstenedione levels compared to an almost 6% daily glucocorticoid dose increase in children assigned to placebo.^[2]

The US Food and Drug Administration (FDA) granted the application for crinecerfont fast track, breakthrough therapy, orphan drug, and priority review designations.^[2] The FDA granted the approval of Crenessity to Neurocrine Biosciences, Inc.^[2]

Society and culture

Legal status

Crinecerfont was approved for medical use in the United States in December 2024.^[1][2][5]

Names

Crinecerfont is the international nonproprietary name.^[6]

Crinecerfont is sold under the brand name Crenessity.^[1]

References

1. ^ Jump up to:^{a b c d e f g} “Crenessity- crinecerfont; capsule Crenessity- crinecerfont solution”. DailyMed. 1 December 2024. Retrieved 25 January 2025.
2. ^ Jump up to:^{a b c d e f g h i j k l m n o p q} “FDA Approves New Treatment for Congenital Adrenal Hyperplasia”. U.S. Food and Drug Administration (FDA) (Press release). 1 October 2024. Retrieved 16 December 2024.  This article incorporates text from this source, which is in the public domain.
3. ^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
4. ^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
5. ^ “Neurocrine Biosciences Announces FDA Approval of Crenessity (crinecerfont), a First-in-Class Treatment for Children and Adults With Classic Congenital Adrenal Hyperplasia” (Press release). Neurocrine Biosciences. 13 December 2024. Retrieved 16 December 2024 – via PR Newswire.
6. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3). hdl:10665/330879.

Further reading

• Auchus, Richard; Chan, Jean; Farber, Robert; Fechner, Patricia; Giri, Nagdeep; Nokoff, Natalie; et al. (1 November 2022). “OR18-4 Crinecerfont (NBI-74788), a Novel CRF1 Receptor Antagonist, Lowers Adrenal Androgens and Precursors in Adolescents with Classic Congenital Adrenal Hyperplasia”. Journal of the Endocrine Society. 6 (Supplement_1): A618. doi:10.1210/jendso/bvac150.1281. PMC 9625506.
• Auchus, Richard J; Sarafoglou, Kyriakie; Fechner, Patricia Y; Vogiatzi, Maria; Giri, Nagdeep; Roberts, Eiry; et al. (8 May 2020). “OR25-03 The Effects of Crinecerfont (NBI-74788), a Novel CRF1 Receptor Antagonist, on Adrenal Androgens and Precursors in Patients with Classic Congenital Adrenal Hyperplasia: Results from A Multiple-Dose Phase 2 Study”. Journal of the Endocrine Society. 4 (Supplement_1): OR25-03. doi:10.1210/jendso/bvaa046.221. PMC 7209526.
• Auchus, Richard J; Sarafoglou, Kyriakie; Fechner, Patricia Y; Vogiatzi, Maria G; Imel, Erik A; Davis, Shanlee M; et al. (17 February 2022). “Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia”. The Journal of Clinical Endocrinology & Metabolism. 107 (3): 801–812. doi:10.1210/clinem/dgab749. PMC 8851935. PMID 34653252.
• Newfield, Ron S; Sarafoglou, Kyriakie; Fechner, Patricia Y; Nokoff, Natalie J; Auchus, Richard J; Vogiatzi, Maria G; et al. (18 October 2023). “Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia”. The Journal of Clinical Endocrinology & Metabolism. 108 (11): 2871–2878. doi:10.1210/clinem/dgad270. PMC 10583973. PMID 37216921.

External links

• “Crinecerfont (Code C174708)”. NCI Thesaurus.
• Clinical trial number NCT03525886 for “Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NBI-74788 in Adults With Congenital Adrenal Hyperplasia” at ClinicalTrials.gov

1. Prete A, Auchus RJ, Ross RJ: Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol. 2021 Nov 30;186(1):R1-R14. doi: 10.1530/EJE-21-0794. [Article]
2. Yogi A, Kashimada K: Current and future perspectives on clinical management of classic 21-hydroxylase deficiency. Endocr J. 2023 Oct 30;70(10):945-957. doi: 10.1507/endocrj.EJ23-0075. Epub 2023 Jun 29. [Article]
3. FDA Approved Drug Products: Crenessity (crinecerfont) capsules/solution for oral administration (December 2024) [Link]
4. FDA News Release: FDA Approves New Treatment for Congenital Adrenal Hyperplasia [Link]

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