Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted

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Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted Thiazole Derivatives via Cyclization Reaction with a Carbamimidothioate Linker Hye-Jin Kwon, Ye-Ji Kim, Si-Yeon Han, and Young-Dae Gong ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00039 • Publication Date (Web): 22 Apr 2019 Downloaded from http://pubs.acs.org on April 25, 2019

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ACS Combinatorial Science

Graphical abstract

Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted Thiazole Derivatives via Cyclization Reaction with a Carbamimidothioate Linker

Hye-Jin Kwon, Ye-Ji Kim, Si-Yeon Han, Young-Dae Gong* Innovative Drug Library Research Center, Department of Chemistry, College of Science, Dongguk University, 30, Pildong-ro 1-gil, Jung-gu, Seoul 04620, Korea O

O

*

O

NH2 O

O

S N H

N

R1 NH2

O

Building Blocks Cleavage

O

R4 R3

S N H

N

R1 NH O

NH R2

36 examples (27-8% yield)

BOMBA resin

Corresponding author. Tel. : +82-2-2260-3206, Fax : +82-2-2290-1349 ; e-mail: [email protected]

1

ACS Paragon Plus Environment

ACS Combinatorial Science 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted Thiazole Derivatives via Cyclization Reaction with a Carbamimidothioate Linker Hye-Jin Kwon, Ye-Ji Kim, Si-Yeon Han, Young-Dae Gong* Innovative Drug Library Research Center, Department of Chemistry, College of Science, Dongguk University, 30, Pildong-ro 1-gil, Jung-gu, Seoul 04620, Korea

Abstract: Preparation of 2,4,5-trisubstituted thiazole derivatives via a new solid-phase synthetic route has been conducted in this study. The synthetic route begins with the synthesis of a core skeleton 2,4diamino(thiazole-5-yl)substituted-phenylmethanone resin, obtained through a cyclization reaction with a carbamimidothioate linker. The core skeleton was substituted with diverse building blocks such as amines, alkyl halides, and acid chlorides. The products were cleaved from the solid support via a TFA/CH2Cl2 cleavage cocktail. Overall, the strategy permits the incorporation of three points of diversity into the thiazole ring system with good overall yields.1 Finally, 2,4,5-trisubstituted thiazole derivatives library showed oral bioavailability through calculation of the physicochemical properties. . KEYWORDS: 2,4,5-Trisubstituted Thiazole, Solid-phase, Carbamimidothioate linker, BOMBA.

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Introduction

Combinatorial chemistry is considered important for new drug discovery.2 Solid-phase synthesis especially, is one of the fastest and easiest tools for the synthesis of libraries of compounds in a short time.3 Among organic small molecules, heterocyclic skeletons, especially five-ring heterocycles, play an important role in medicinal chemistry because heterocyclic derivatives help elicit the pathways of complicated biological mechanisms and have demonstrated a broad range of important biological activities4 like anti-inflammatory (Meloxicam)5, antifungal (Fluconazole)6, anticancer (Lapatinib)7. For instance, Roscovitine,8 one of the heterocycle derivatives, is a biological inhibitor targeting cyclin dependent kinase (CDK)9 and glycogen synthase kinase-3 (GSK-3),10 involved in cells’ mRNA processes, transcription and cellular differentiation. Figure 1 shows Structure of five membered heterocyclic derivatives with diverse functional groups. O N

OH O

O

S

N O

N H

O

N N S

HO F

N

N N

S

F O

NH N

O

HN

F

N

Fluconazole6

Lapatinib7

N

N

Cl

N Meloxicam5

HN

OH

N H

N

N

Roscovitine8

Figure 1. Structure of five membered heterocyclic derivatives with diverse functional groups

In previous studies, 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives were discovered as hit compounds using high throughput screening techniques11 and possess highly potent antiinflammatory biological activities toward sphingosylphosphorylcholine (SPC). SPC plays a multifunctional role in such biological activities as cell growth, differentiation, calcium signaling, and tissue remodeling.12 Therefore, we attempted to optimize biological activities toward SPC by synthesizing 2,4,5-trisubstituted thiazole derivatives using solid-phase synthesis strategy introducing 3



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the sulfone traceless linker1, 13 to the Merrifield resin as shown in Scheme 1 (a). We found that the SPC receptor inhibition rate was varied by the type of secondary amines via a cell test of 2,4,5trisubstituted thiazole derivatives library.11 It means that secondary amines play an important role in determining the inhibition rate. However, as the sulfonyl linker act as electrophile, the introduced substituent was limited to the amine group, and this methodology makes it difficult to increase the diversity of the library. To overcome this problem, we introduced a new carbamimidothioate linker14 to the Merrifield resin which act as a nucleophile, allowing the introduction of various electrophile substituents, such as alkyl halides and acid chlorides while keeping the secondary amine group which is the key factor of the compound (Scheme 1 (b)). Additionally, For the construction of more diverse library, we try to introduce the urea form at 4amine position instead of acyl group. Urea group is generally well used substituent in developing new drug. For example, regorafenib,15 the multi-kinase inhibitor, is one of the drugs which contains urea group. Also, oxygen and nitrogen in urea moiety form inter and intra molecular hydrogen bonding, and it can increase the interaction with the drug target. As a result, we expect an improved molecular diversity of the 2,4,5-trisubstituted thiazole library which can serve more effectively in the development of potential SPC receptor inhibitors. Herein, we report our recent progress on this topic.

Scheme 1. Strategy of synthesize various 2,4,5-trisubstituted thiazoles via carbamimidothioate linker (a) Our previous method

O N S

CN

BrCH2COR1

S

SH O

S

O

N

O

R1 1) R2COCl

NH2

R3

2) R3NH2

S N H

N

R1 N H

R2

New approach (b) Our Present method N

OMe

O

N H 3

O

CN SH

BrCH2COR1

OMe

O

S N H

N

O

R1 OMe

NH2 O

4

S N H

4


5

N

R1 N O

O OPh OPh

1) R2NH2 2) R3Cl / R4COCl

O

O R4

R3

S N H

N

R1 NH

9, 10 O

NH R2

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Results and Discussion

The overall synthetic strategy used to prepare the target 2,4,5-trisubstituted thiazole analogues 9 and 10 is outlined in Scheme 2 and Figure 2. The initial solid-phase synthetic route involved the formation of the intermediate thiazole resin 4 from solid-supported carbamimidothioate linker 3, which is derived from the isothiocyanate terminated resin 2 and cyanamide. Treatment of intermediate resin 3 with various 2-bromoacetophenones followed by cyclization, produces the key intermediate thiazole resins 416 while concurrently effecting the first diversification. Next, phenylchloroformate was added to the resin 4 generating the resin 5. The second diversification of the intermediate resin was accomplished by reacting resin 5 with primary amines to afford the urea functionalized resin 6.17 The final diversification was accomplished by N-Alkylation and N-Acylation of the resin 6, producing resin 7 and 8, respectively.14a, 14d Finally, representative resins 7 and 8 were treated with diluted trifluoroacetic acid (TFA) to form 2-amino- and 2-amido-substituted thiazoles 9 and 10, respectively.

Scheme 2. Solid-phase synthetic route of the various 2,4,5-trisubstituted thiazole librariesa O

O

(a)

NH2

NCS O

O

HN

O (h)

NH

N

R3

NH

O

O

S

O S HN O

N R4

O (h)

NH O

10

NH R2

O

S N

N O

O

R4

SH

N

N H

R1 NH2

4

(d)

NH

O

NH R2

R1

O

S N H

N

6

(g)

NH O

S

(f)

O

R1

O

3

7

9

(c)

R1

O

R3

O

R2

N

N

O

CN

O

2

R1

S

N H

O

1

O

+ NH2CN

N

O

(b)

NH R2

8

5


O

R1 NH O

O

(e) NH R2

O

R1

S N H

5

N

N O

O OPh OPh


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Reagents and conditions : (a) carbon disulfide, Et3N, p-TsCl, THF, rt, 10 h; (b) DBU, THF, rt, 2 h; (c) 2bromoacetophenone, DBU, THF, rt, 2 h; (d) phenylchloroformate, pyridine, CH2Cl2, rt, 2 h; (e) amine, DMSO, rt, 2 h; (f) alkyl chloride, t-BuOK, THF, 60 ℃, 16 h; (g) acid chloride, pyridine, DMAP, 60 ℃, 12 h; (h) TFA:CH2Cl2 (1:3, v/v), 40 ℃, 6 h. a

- a-Bromoketones (R1 ) O Br

O

Br

NC 2

1 - Amines (R2 )

NH2

NH2

NH2

NH2

O 1 - Alkyl halides (R3 )

2

4

3

Cl

Cl

Cl

O 1

3

2

- Acid chlorides (R4 ) O

O

O

Cl

Cl

Cl

O 1

2

3

Figure 2. Building block for 2,4,5-substituted thiazole derivatives.

In solid-phase, parallel synthesis methodology, the isothiocyanate terminated resin 2 was selected as a polymer support because it can be readily reacted with cyanamide and 2-bromoacetophenone to form the key intermediate resin which have secondary amine group. The isothiocyanate terminated resin 2 was formed by treatment of the 4-benzyloxy-2-methoxybenzylamine (BOMBA)18 resin 1 with carbon disulfide (CS2) in the presence of triethylamine (Et3N) in tetrahydrofuran (THF) at room temperature, based on Wong’s solution-phase synthesis.19 The formation of resin 2 was confirmed by inspection of its attenuated total reflection (ATR) bead FT-IR spectrum, which showed the presence of the typical isothiocyanate band at 2068 cm-1 (Figure S4(A)). At first, resin 4 was formed by the in situ reaction of resin 2. But, it was found through several experiments that resin 4 was formed better when we added 6


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a washing step after resin 3 was synthesized from resin 2, signaled by the presence of the C≡N band at 2147 cm-1 and C=N band at 1646 cm-1, and the absence of the isothiocyanate band for resin 2 at 2068 cm-1 (Figure S4(B)). Thus, the resin bound isothiocyanate reacted with cyanamide in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in THF at room temperature to give resin 3, then resin 3 reacted with 2-bromoacetophenone in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in THF at room temperature to form the resin bound 2,4-diamino(thiazole-5-yl)substitutedphenylmethanone 4 as a key core skeleton, signaled by the absence of the C≡N band for 2 at 2147 cm1

(Figure S4(C)). In this step, for the first diversification of resin 4, we used two kinds of 2-

bromoacetophenone. To develop the solid-phase synthesis methodology for cyclization of the carbamimidothioate linker resin 3, a number of different activating bases, like potassium tert-butoxide (t-BuOK), sodium hydride (NaH) and DBU were investigated and the conversion rate of resin 3 was checked by LC-MS after cleavage from the resin 4{1} by treatment with TFA in CH2Cl2. The results are given in Table S1 and Figure S1. This process showed that the best condition for cyclization involved the use of DBU in THF at room temperature. This process led to more effective formation of the

2,4-diamino(thiazole-5-yl)substituted-phenylmethanone

4.

Next,

we

introduced

phenylchloroformate to the resin 4, which selectively reacts with the 4-amino group. The reaction proceeded in the presence of pyridine in CH2Cl2 at room temperature. It’s FTIR spectrum showed two weak C=O bands at 1762 cm-1 and 1722 cm-1 (Figure S4(D)). We using cozy spectra explained the regioselectivity of phenylchloroformate to 4-amino group. In Figure S2, we can see the peak corresponding to vicinal coupling between Ha and Hb in intermediate 4’. After the reaction between derivative 4’ and phenylchloroformate, if the phenylchloroformate didn’t have any regioselectivity to 4-amino group, the peak of vicinal coupling will not be found in cozy NMR spectrum of derivative 5’ because Hb will be not appear during the reaction. But in the Figure S3, we can still find the vicinal coupling peak of Ha and Hb which explains the regioselectivity of phenylchloroformate to 4-amino group.14d For the second diversification of the 4-amino group, resin 5 was treated with several amines in the 7



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presence of DMSO at room temperature to yield resin 6 with a urea moiety. The reaction was also monitored by ATR-FTIR spectroscopy, which showed the shift of C=O band from 1762 cm-1 and 1722 cm-1 to 1684 cm-1 (Figure S4(E)). For the third diversification of the 2-secondary amine portion, various electrophiles, such as alkyl halides and acid chlorides were introduced to the 2-substituted alkylamino-4-urea(thiazole-5-yl)substituted-phenylmethanone resin 6. First, alkylation of the 2-substituted alkylamino-4-urea(thiazole-5-yl)substituted-phenylmethanone resin 6 in the presence of t-BuOK in THF at 60 ℃ for 16 h produced the desired 2,2-disubstituted alkylamino-4-urea(thiazole-5-yl)substituted-phenylmethanone resin 7. This process was monitored using ATR-FTIR, which showed the absence of the band at 1684 cm-1 (Figure S4(F)). In the last step, the 2-substituted alkylamino-4-urea(thiazole-5-yl)substituted-phenylmethanone derivatives 9 were formed by cleavage of resin 7 via treatment with TFA in CH2Cl2. As shown in Table 1, the desired various 2-substituted alkylamino-4-urea(thiazole-5-yl)substituted-phenylmethanone derivatives 9 can be produced by this seven-step route with good overall yields1, 13 and purities. Table 1. Yields and purities of the 2-substituted alkylamino-4-urea(thiazole-5-yl)substitutedphenylmethanone derivatives 9a No. {R1,R2,R3}

Yield (%)

Purity (%)

No. {R1,R2,R3}

Yield (%)

Purity (%)

9 {1,1,1}

12.3

95.40

9 {2,1,1}

12.4

100

9 {1,1,2}

14.3

90.93

9 {2,1,2}

14.1

98.36

9 {1,1,3}

8.6

100

9 {2,1,3}

15.3

95.51

9 {1,2,1}

17.8

94.53

9 {2,2,1}

15.7

90.14

9 {1,2,2}

13.7

100

9 {2,2,2}

12.2

100

9 {1,2,3}

9.2

94.79

9 {2,2,3}

11.7

100

9 {1,3,1}

13.2

100

9 {2,3,1}

10.8

100

9 {1,3,2}

14.3

100

9 {2,3,2}

17.4

91.80

8


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9 {1,3,3} a

10.4

9 {2,3,3}

100

12.4

93.56

Yield was calculated over seven steps, and purity was checked by LC-MS at 254 nm

Next, the 2-substituted alkylamino-4-urea(thiazole-5-yl)substituted-phenylmethanone resin 6 provided

the

desired

2-alkylamino-2-substituted

amido-4-urea(thiazole-5-yl)substituted-

phenylmethanone resin 8 by acylation reaction of resins 6 with acid chlorides in the presence of pyridine and DMAP at 60 ℃ for 12 h. The progress of this reaction was monitored by ATR-FTIR spectroscopy, but there was no prominent change detected by IR spectrum (Figure S4(G)). This 2alkylamino-2-substituted amido-4-urea(thiazole-5-yl)substituted-phenylmethanone resin 8 easily yielded the 2-substituted amido-4-urea(thiazole-5-yl)substituted-phenylmethanone derivatives 10 by cleavage from resin 8 upon treatment with TFA in CH2Cl2. As shown in Table 2, 2-substituted amido4-urea(thiazole-5-yl)substituted-phenylmethanone derivatives 10 can be produced with good overall yields and purities. Table 2. Yields and purities of the 2-substituted amido-4-urea(thiazole-5-yl)substitutedphenylmethanone derivatives 10a No. {R1,R2,R3}

Yield (%)

Purity (%)

No. {R1,R2,R3}

Yield (%)

Purity (%)

10 {1,1,1}

13.8

100

10 {2,1,1}

9.2

91.02

10 {1,1,2}

23.2

100

10 {2,1,2}

17.2

92.67

10 {1,1,3}

24.1

100

10 {2,1,3}

24.9

95.65

10 {1,3,1}

8.3

90.28

10 {2,3,1}

12.7

90.56

10 {1,3,2}

16.4

100

10 {2,3,2}

21.6

93.02

10 {1,3,3}

13.7

100

10 {2,3,3}

26.9

100

10 {1,4,1}

11.7

97.28

10 {2,4,1}

13.7

98.99

10 {1,4,2}

11.8

100

10 {2,4,2}

18.1

100

9



10 {1,4,3} a

20.6

10 {2,4,3}

100

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24.6

100

Yield was calculated over seven steps, and purity was checked by LC-MS at 254 nm

To determine the drug like properties of 2,4,5-trisubstituted thiazole library, physicochemical descriptor was calculated using Discovery studio 2018 in Figure 3. As a rule of thumb, orally absorbed drugs tend to obey what is known as Lipinski’s rule of five. The rule included the following condition: a molecular weight should be no more than 500, hydrogen bond donor group should be less than 5, hydrogen bond acceptor group should be less than 10. A calculated log P value should be no more than +5 which is a measure of a drug’s hydrophobicity, a polar surface area should be less than 140 Å. At last, rotatable bond should be less than 10. 20 In the Figure 3, the vertical axis of graph indicates the number of compounds that within each range of condition. We can see the most of derivatives satisfy the Lipinski’s rule and it implies the library has a potential as orally active drug. Additionally, Figure 4 show us the polar surface area and 3D structure of representative compounds. Polar surface area is the key factor to determine the interaction between the drug and drug target. A relatively polar part is indicated by red color, and the blue color represents a relatively nonpolar part. Most of compounds seems have the similar polar surface area and structures. So, we can expect that improved diversity of substituent can affect the inhibitor rate of SPC receptor under the similar condition of polar surface area and structure.

10


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AlogP

Molecular weight

13

15

30

10

9

10

24

20 11

5

2

0

10

2

0

3.5< 4< 4.5< 5< 5.5< 6< 6.5

Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted

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