2-Propenamide, N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl]-2-pyrimidinyl]amino]-4-methoxy-2-(4-morpholinyl)phenyl]

Partition coefficient

Administrative data

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 Oct 2020 to 01 Dec 2020

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPPTS 830.7570 (Partition Coefficient, n-octanol / H2O, Estimation by Liquid Chromatography)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: EC Guideline A.24. Partition Coefficient (n-octanol/water), High Performance Liquid Chromatography (HPLC) Method

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

HPLC method

Test material

Test material information

Constituent 1

Reference substance name:

N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}pyrimidin-2-yl)amino]-4-methoxy-2-(morpholin-4-yl)phenyl}prop-2-enamide

EC Number:

841-500-6

Cas Number:

1903008-80-9

Molecular formula:

C30H34N8O3

IUPAC Name:

N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}pyrimidin-2-yl)amino]-4-methoxy-2-(morpholin-4-yl)phenyl}prop-2-enamide

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- lot/batch number of test material: M20BD0542
- Expiry date: 19 February 2022 (retest date)
- Physical Description: Slightly greenish yellow powder
- Purity: 99.8%
- Purity correction factor: 1.00

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature

Study design

Analytical method:

high-performance liquid chromatography

Results and discussion

Partition coefficient

Partition coefficient 1

Key result

Type:

log Pow

Partition coefficient:

4.9

pH:

11

Remarks on result:

other: Value corresponding to major peak observed on the chromatogram.

Partition coefficient 2

Type:

log Pow

Partition coefficient:

5.6

pH:

7

Remarks on result:

other: Column temperature was 35°C ± 1°C

Details on results:

Calculation method
The Pow of the test item was calculated to be 2.9 x 10E3 (log Pow 3.5) using the Rekker calculation method.
No pKa values for acidic groups in the molecular structure of the test item in the logarithm
range of 1 - 14 were calculated.
The pKa values in the logarithm range of 1 - 14 for basic groups in the molecular structure of
the test item were calculated using the Perrin calculation method. Two basic groups were identified in the molecular structure of the test item, which had pKa values of 2.0 and 8.9.

Main study

pH 7
In the chromatogram of the test solution, one test item peak was observed. The equation of the
regression line was: log k’ = 0.324 × log Pow – 0.814 (r = 0.993, n = 12). Detailed results are given in the table in the field 'Any other information on results incl. tables'.


pH 11
In the chromatogram of the test solution, one test item peak was observed. The equation of the
regression line was: log k’ = 0.327 × log Pow – 0.982 (r = 0.98, n = 12). Detailed results are given in the table in the field 'Any other information on results incl. tables'.

Any other information on results incl. tables

P_OW of the test item - ph 7

Substance	Retention time (min)			Log POW	POW
	tr,1 [min]	tr,2 [min]	mean tr (n=2)
Formamide (t0)	0.605	0.606	0.606
Benzylalcohol	0.772	0.774		1.1
Toluene	1.477	1.477		2.7
1,4-Dichlorobenzene	1.888	1.888		3.4
Dibenzyl	4.117	4.110		4.8
Triphenylamine	7.487	7.467		5.7
4,4’-DDT	10.527	10.508		6.5
Test item	6.552	6.542	6.547	5.6	3.7 x 10^5

 

P_OW of the test item – pH 11

Substance	Retention time (min)			Log POW	POW	Peak area (%)
	tr,1 [min]	tr,2 [min]	mean tr (n=2)
Formamide (t0)	0.588	0.620	0.604
Benzylalcohol	0.701	0.705		1.1
Toluene	1.279	1.280		2.7
1,4-Dichlorobenzene	1.605	1.604		3.4
Dibenzyl	3.097	3.081		4.8
Triphenylamine	5.142	5.126		5.7
4,4’-DDT	7.352	7.367		6.5
Test item – peak 1	1.305	1.309	1.307	3.2	1.6 x 10^3	4.2
Test item – peak 2	2.574	2.566	2.570	4.6	3.7 x 10^4	0.78
Test item – peak 3	3.192	3.183	3.188	4.9	8.6 x 10^4	95

 

Applicant's summary and conclusion

Conclusions:

The HPLC method at pH 7 and pH 11 was applied for the determination of the partition coefficient (Pow) of JNJ-73841937-AAA (T003925).
The log Pow value of the test item at pH 7 was 5.6. The log Pow values of the test item at pH 11 were 3.2, 4.6 and 4.9 for peak 1, 2 and 3, respectively.

Experimentally obtained log Pow values are different compared to log Pow values obtained using the calculation method. The calculation method was based on the theoretical fragmentation of the molecule. Taking into consideration predicted pKa values it was expected that molecule is in non-ionized form at pH 11 and in ionized form at pH 7 (environmentally relevant pH). Therefore it was expected that log Pow value at pH 11 is higher than log Pow value at pH 7.