WO2001016115A1

WO2001016115A1 - Process for synthesizing isoxazolidines

Info

Publication number: WO2001016115A1
Application number: PCT/US2000/024149
Authority: WO
Inventors: Charles R. Johnson; Birong Zhang
Original assignee: Chemrx Advanced Technologies, Inc.
Priority date: 1999-09-01
Filing date: 2000-08-31
Publication date: 2001-03-08
Also published as: AU7105800A

Abstract

The present invention provides a process for synthesizing a compound or an array of compounds of Formula (I) and formula(-4).

Description

PROCESS FOR SYNTHESIZING ISOXAZOLIDINES

FIELD OF INVENTION

The present invention relates to a process for the synthesis of isoxazolidines.

BACKGROUND OF THE INVENTION

This invention relates to synthesis of isoxazolidine based compounds. United States Patent No. 5,153,193 discloses isoxazolidine compounds useful in treating memory dysfunctions characterized by a cholinergic effect such as Alzheimers disease. Isoxazolidine compounds are also known to have potential utility for the treatment of anxiety and for the improvement of learning disabilities.

As discussed above, isoxazolidine based compounds possess useful biological activity. Efforts continue to make a wider variety of compounds having a isoxazolidine nucleus. Current synthetic methods useful in making isoxazolidine derivatives are slow and time consuming. There is thus a need for a new process that will synthesize a plurality of isoxazolidine compounds in a short amount to time. Such an array or library of compounds can then be evaluated for its biological activity.

SUMMARY OF THE INVENTION

Keeping the above discussed needs in mind the present invention provides a process for synthesizing a compound or an array of Isoxazolidine based compounds of Formula I. Also provided by the present invention are novel compounds of formula-4 and a process to make the same. The compounds of formula-4 are useful in synthesizing isoxazolidine based compounds as described by the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for synthesizing a compound or an array of compounds of Formula I

.Formula I wherein

R¹ is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;

R² is selected from (CH₂)_0-6 aryl, (CH₂)o-₆ substituted aryl, Cι-C₄ alkyl, (CH₂)_0-6 heteroaryl and (CH₂)_0-6 heterocyclyl;

R³ and R⁴ independently at each occurance represent a group capable of forming a stable bond with the nitrogen atom to which they are attached; alternatively

R³ and R⁴ along with the nitrogen atom to which they are attached can form a heterocyclyl ring;

R^J is selected from H, COOR , 10 , CO-alkyl, CON(R 1^l0^u)x₂ and CO-aryl ;

R⁶ is selected from H, aryl, Cj. alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH )ι_-4 aryl; and

R¹⁰ independently at each occurance represents C_1-4 alkyl, aryl, H or heterocyclyl; said process comprising

(i) treating, in an a suitable solvent, a compound or an array of compounds of formula-2

.formula-2

with a compound of formula-3

.formula-3

where R¹, R², R⁵ and R⁶ are defined above, and SS represents a solid support, to form a compound or an array of compounds of formula-4

.formula-4

where R¹, R², R⁵, R⁶ and SS are as defined above;

(ii) treating a compound or an array of compounds of formula-4 in succession with (a) a solution of a protonating agent in an inert medium; and

(b) an inert solvent solution of an alkylating agent, to form a compound or an array of compounds of formula-5,

.formula-5

where R¹, R², R⁵, R⁶ and SS are as defined above, and ALKYL represents methyl, CH₂-TMS or CH₂-CN;

(iii) treating, in an inert medium and in the presence of a base, a compound or an array of compounds of formula-5 with an amine of formula-6

R³R⁴NH .formula-6 where R³ and R⁴ are as defined above, to form a compound or an array of compounds of Formula I.

A preferred aspect of the present invention provides a process wherein R¹ is selected from H, C_1-6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, C_1-4 alkoxy, phenyl, C_1-4 alkyl and C_3-8 branched alkyl; heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from

R is selected from (CH₂)i-₃ aryl,

Cι_-4 alkyl,

(CH₂)_1-3 heteroaryl, and

(CH₂)_1-3 substituted aryl, said aryl substituted with one to five substituents selected from OC_1-3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO₂, Cι_-4 alkyl, phenyl, SC alkyl, NH₂, NHCι_-4 alkyl, N(C_1-4 alkyl)₂ and CF₃;

R³ and R⁴ are independently selected from H, Cι_₆ alkyl,

1 -(N,N-dimethyl)-prop-2-yl ,

2-dimethylamino-l-methyl-ethyl,

3-pyrrolidin- 1 -yl-propyl, 2-morpholin-4-yl -ethyl,

2-(4-methyl-piperazin-l-yl)-ethyl,

4-diethylamino- 1 -methyl-butyl,

2-diethylamino-ethyl,

2-hydroxy-butyl, 3-methoxy-propyl, cyclohexyl, tetrahydro-furan-2-ylmethyl, benzyl,

2-amino benzyl, 2-fluoro benzyl,

2-oxo-azepan-3-yl,

2-(2-oxo-pyrrolidin- 1 -yl)-ethyl ,

2-(3,4-dimethoxy-phenyl)-ethyl,

2-(3a,7a-dihydro-lH-indol-3-yl)-ethyl, 2-hydroxy-cyclohexyl,

1 -benzyl-2-hydroxy-ethyl,

5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl,

4-methyl-benzyl,

2-amino-3-fluoro-benzyl, 3-hydroxy-2,2-dimethyl-propyl,

2-(2-hydroxy-ethoxy)-ethyl, and

2-hydroxy-ethyl;

R⁵ is selected from H, COOH, COC₂H₅, CO-aryl and COCH₃; and

R⁶ is selected from H, Ph, CH₃, C₂H₅, aryl, CF₃ and benzyl. A further preferred embodiment provides a process wherein step(i) is carried out in a suitable solvent selected from DMF, DMSO, toluene, DMA, THF, DCM and

NMP, at a temperature of from about 40°C to about 120°C; and step (iii) is carried out in the presence of a base selected from pyridine, triethyl amine, lutidine, trimethyl amine or excess of an amine of formula-6. Yet another preferred embodiment provides a process wherein step (i) is carried out in a suitable solvent selected from DMF,

DMSO and toluene, at a temperature of from about 70°C to about 100°C.

Another aspect of the present invention provides an array of compounds of

Formula I

.Formula I

wherein

R² is selected from (CH₂)_0-6 aryl, (CH₂)₀.₆ substituted aryl, Cι-C₄ alkyl, (CH₂)_0-6 heteroaryl and (CH₂)o_-6 heterocyclyl;

R³ and R⁴ independently at each occurance represent a group capable of forming a stable bond with the nitrogen atom to which they are attached; alternatively R³ and R⁴ along with the nitrogen atom to which they are attached can form a heterocyclyl ring;

R⁵ is selected from H, COOR¹⁰, CO-alkyl, CON(R¹⁰)₂ and CO-aryl ;

R⁶ is selected from H, aryl, C_1-4 alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH₂)_1- aryl; and R¹⁰ independently at each occurance represents C_1-4 alkyl, aryl, H or heterocyclyl.

In yet another aspect of the invention is provided an array of compounds of formula-4, wherein

R¹ is selected from H, Cι_-6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, C_1-4 alkoxy, phenyl, C_1- alkyl, C_3-8 branched alkyl and CN, heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from

R² is selected from

(CH₂)_1-3 aryl,

C_1-4 alkyl, (CH₂)ι.₃ heteroaryl, and

(CH₂)_1-3 substituted aryl, said aryl substituted with one to five substituents selected from OC_1-3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO₂, C_1-4 alkyl, phenyl,

SC_1-4 alkyl, NH₂, NHd_-4 alkyl, N(C_1-4 alkyl)₂ and CF₃;

R³ and R⁴ are independently selected from H, C_1-6 alkyl, l-(N,N-dimethyl)-prop-2-yl,

2-dimethylamino-l-methyl-ethyl,

3-pyrrolidin- 1 -yl-propyl ,

2-mo holin-4-yl-ethyl,

2-(4-methyl-piperazin-l-yl)-ethyl, 4-diethylamino-l -methyl-butyl,

2-diethylamino-ethyl ,

2-hydroxy-butyl,

3-methoxy-propyl, cyclohexyl, tetrahydro-furan-2-ylmethyl, benzyl,

2-amino benzyl,

2-fluoro benzyl,

2-oxo-azepan-3-yl, 2-(2-oxo-pyrrolidin- 1 -yl)-ethyl,

2-(3,4-dimethoxy-phenyl)-ethyl,

2-(3a,7a-dihydro-lH-indol-3-yl)-ethyl,

2-hydroxy-cyclohexyl, l-benzyl-2-hydroxy-ethyl, 5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl,

4-methyl-benzyl,

2-amino-3-fluoro-benzyl, 3-hydroxy-2,2-dimethyl-propyl,

2-(2-hydroxy-ethoxy)-ethyl, and

2-hydroxy-ethyl;

R⁵ is selected from H, COOH, COC₂H₅, CO-aryl and COCH₃; and

R⁶ is selected from H, Ph, CH₃, C₂H₅, aryl, CF₃ and benzyl.

Also provided in another aspect of the present invention is provided a process for synthesizing a compound or an array of compounds of formula-4

.formula-4

wherein

R² is selected from (CH₂)₀.₆ aryl, (CH₂)o.₆ substituted aryl, Cι-C₄ alkyl, (CH₂)_0-6 heteroaryl and (CH₂)₀-₆ heterocyclyl;

R³ and R⁴ along with the nitrogen atom to which they are attached can form a heterocyclyl ring; R⁵ is selected from H, COOR¹⁰, CO-alkyl, CON(R¹⁰)₂ and CO-aryl ;

R⁶ is selected from H, aryl, Cι_-4 alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH₂)_1-4 aryl;

R¹⁰ independently at each occurance represents Cι_-4 alkyl, aryl, H or heterocyclyl; and

SS represents a solid support; said process comprising treating, in an a suitable solvent, a compound or an array of compounds of formula-2

.formula-2

with a compound of formula-3

.formula-3

where R¹, R², R⁵ and R⁶ are defined above, and SS represents a solid support, to form a compound or an array of compounds of formula-4, where R¹, R², R , R and

SS are as defined above. A preferred process is one wherein R¹ is selected from H, Cι_-6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, Cι_-4 alkoxy, phenyl, Cι_-4 alkyl, C_3-8 branched alkyl and CN, heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from

R is selected from (CH₂)_1-3 aryl, C_1-4 alkyl, (CH₂)_1-3 heteroaryl, and (CH₂)ι.₃ substituted aryl, said aryl substituted with one to five substituents selected from OCj_-3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO₂, Cι_-4 alkyl, phenyl,

SC alkyl, NH₂, NHC_1-4 alkyl, N(C_M alkyl)₂ and CF₃;

2-dimethylamino- 1 -methyl -ethyl,

3-pyrrolidin- 1 -yl-propyl,

2-morpholin-4-yl-ethyl,

2-(4-methyl-piperazin-l-yl)-ethyl, 4-diethylamino-l -methyl-butyl,

2-diethylamino-ethyl,

2-hydroxy-butyl,

3 -methoxy-propyl , cyclohexyl, tetrahydro-furan-2-ylmethyl, benzyl,

2-amino benzyl,

2-fluoro benzyl,

2-oxo-azepan-3-yl, 2-(2-oxo-pyrrolidin-l-yl)-ethyl,

2-(3,4-dimethoxy-phenyl)-ethyl,

2-(3a,7a-dihydro-lH-indol-3-yl)-ethyl,

4-methyl-benzyl,

2-amino-3-fluoro-benzyl,

3-hydroxy-2,2-dimethyl-propyl,

2-(2-hydroxy-ethoxy)-ethyl, and 2-hydroxy-ethyl;

R⁵ is selected from H, COOH, COOCH₃ and COCH₃; and

R⁶ is selected from H, Ph, CH₃, C₂H₅, aryl, CF₃ and benzyl. A preferred embodiment provides a process for synthesizing compounds of formula-4 wherein step(i) is carried out in an inert medium selected from DMF, DMSO, toluene, DMA, THF, DCM and NMM, at a temperature of from about 40°C to about 120°C. In a further preferred process step (i) is carried out in an inert medium selected from DMF, DMSO and toluene, at a temperature of from about 70°C to about 100°C.

Another aspect of the present invention provides a compound or an array of compounds of formula-4

wherein

R is selected from (CH₂)o-₆ aryl, (CH₂)_0-6 substituted aryl, C]-C₄ alkyl, (CH₂)o_-6 heteroaryl and (CH₂)_0-6 heterocyclyl;

R⁵ is selected from H, COOR¹⁰, CO-alkyl, CON(R¹⁰)₂ and CO-aryl ;

R⁶ is selected from H, aryl, Cι- alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH₂)ι_-4 aryl;

SS represents a solid support.

Experimental

The process of the present invention is further illustrated by the following reaction scheme.

Scheme-I:

formula-4

STEP-1: Formula-4:

A compound of formula-2 (swelled with DMF) is mixed with a compound of formula-3. This mixture is heated at a temperature of from about 80°C to about 100°C for up to lh in a ventilated reaction vessel. This heated reaction mixture then is heated from about 15 h to about 72 h in a closed reaction vessel. The reaction mixture is cooled to ambient temperature, rinsed with DMF (x2) and DCM (x2). The rinsed reaction mixture is dried to yield a compound of formula-4. STEP-2: formula-5

A compound of formula-4 from above is treated with a solution of a protonating agent, e.g., TFA, in an inert solvent, e.g., DCM, for about 1-5 minutes. The reaction solids are isolated and washed with DCM. These washed reaction solids are treated with a alkylating agent, e.g., TMS-diazomethane (2.0 M in hexanes) for up to about 15 minutes. The reaction solids are isolated and washed with DCM (x 3-5). The solids are dried to yield a compound of formula-5.

STEP-3: Formula I: A compound of formula-5 is mixed in an inert solvent with a compound of formula-6, in the presence of a base, e.g., pyridine. The reaction mixture is agitated from about 12 to about 72 h at a temperature of from about 20° to about 50°C. The reaction mixture is filtered, the reaction solids are washed with a 1:9; MeOH:CH₂Cl mixture (x2), the combined extracts are concentrated to yield a compound of Formula I.

Starting Materials

Compounds of formula-2:

Compounds of formula-2 are prepared by treating sulfonamide based solid supports (or resins) with an α,β unsaturated acid in the presence of a coupling agent, catalyst (e.g., DIC) and a base (e.g., DMAP, DIPEA) in an inert medium, e.g., DCM. The reaction mixture is gently agitated for 12 to 36 h. The reaction solids are sequentially washed with DCM (x2) and MeOH (x2). The washing sequence is repeated up to 4 times. The washed solids are dried to yield a compound of formula-2.

Compounds of formula-3

Compounds of formula-3 are nitrones. The nitrones are prepared using the procedure described by Confalone and Huie in Organic Reactions, Vol. 36, Chapter 1, John Wiley & Sons, which is incorporated herein by reference. The procedure essentially comprises treating an aldehyde, e.g., glyoxylic acid monohydrate, with hydroxyl amine in DMF (solvent). The reaction mixture is agitated from about 10 to about 20 minutes, filtered and the filtrate is concentrated to form the corresponding nitrone, e.g., compound of formula-3.

Alkylating Agents These agents are used in STEP-2 and are commercially available from sources like Aldrich Chemicals, Fluka and Lancaster.

Compounds of formula-6

Compounds of formula-6 are some times also referred to as cleaving amines. These compounds are primary or secondary amines which can be prepared by methods known to one skilled in the art. The primary and secondary amines of formula-6 also are available from commercial sources such as Aldrich Chemicals, Fluka and

Lancaster.

Synthetic procedure for synthesizing an array of compounds of Formula I. STEP-1: formula-4

The resin (compound of formula-1; 0.15 g) is placed in each well of a Polyfiltronics plate. The resin is swelled with DMF. The Polyfiltronics plate is placed in an open clamp with the wells open at the top and closed at the bottom. A THF solution of a compound of formula-2 (nitrones, 1.0 mL; IM) is added to each well. The Polyfiltronics plate is sealed from the top, placed on its side and shaken on a platform shaker from about 10 to about 30 minutes. The Polyfiltronics plate then is placed horizontally. The plates are vented and placed in an oven, preheated to about 95°C, for about 30 minutes or until gas evolution ceases. These plates then are clamped shut, and heated at about 90-95°C from about 12 to about 72 hours. The plates are cooled to ambient temperature and the resin from each well is rinsed in succession with DMF (x2) and DCM (x2) to yield an array of compounds of formula-4. STEP-2: formula-5

Compounds of formula-4 in each well from the Polyfiltronics plate are treated with a protonating agent, e.g., 1% TFA in DCM (1 mL), for about 10 minutes. The protonating agent is drained, and the contents of each well are rinsed with DCM (x4). The Polyfiltronic plate is reclamped using an open clamp, and an alkylating agent, e.g., a THF solution of TMS-diazomethane (1 mL; Aldrich, 2M in THF), is added to each well. The resulting well contents are let stand from about 5 to about 20 minutes. The resin from each well is rinsed with DCM (x4) to yield a compound of formula-5.

STEP-3: Formula-I

The Polyfiltronic plate comprising wells containing a compound of formula-5, from above, is placed into an open clamp. The bottom of the Polyfiltronics plate is sealed with a Teflon sheet. A solution of an appropriate cleaving amine (formula-6; 0.4 M, 1.0 mL) in anhydrous pyridine is added to each row of wells of the Polyfiltronic plate. The plate is sealed from the top and the contents of the plate wells agitated from about 12 to about 72 hours at ambient temperature. The plate then is frozen in dry ice for about 30 minutes, undamped and placed on top of a 2 mL Beckman deepwell microtiter Beckman collection plate. The polyfiltronics plate is thawed and the liquid contents of each well are drained into the collection plate. The solid contents of each well are rinsed with a mixture of MeOH:CHCl₃; 1:9 (2 x 0.5 mL) and the elute is collected in the same Beckman collection plate. The contents of each well from the Beckman collection plate are concentrated to yield a compound of Formula I.

Purification The above synthesized compounds can be purified by using purification techniques known to one skilled in the art. One such technique is the Supported Liquid-Liquid Extraction (SLE). The SLE technique is especially useful in purifying compounds of Formula I, prepared in STEP-3 above. The SLE process is influenced by the solubility characteristics of the cleaving amines (formula-6) used in STEP-3. For water soluble cleaving amines, i.e., hydrophilic amines, the SLE uses water as the wetting (activating) agent for the SLE material, for e.g., hydromatrix diatomaceous earth. When the cleaving amine is water insoluble , i.e., hydrophobic amines, the SLE material, for e.g., hydromatrix diatomaceous earth is wetted (activated) using 2 N HC1. Details of the SLE process are as described by Charles Johnson in Tetrahedron, 54 (1998) 4097-4106 which are incorporated herein by reference. Specific Examples: The following isoxazolidine compounds were prepared using the process of the present invention.

Standard-A

Η NMR (DMSO-cfe) δ : 8.56 (bs, 1 H), 7.39 - 7.18 (m, 15 H), 5.25 (bs, 1 H), 4.40 - 4.22 (m, 2 H), 4.10 - 4.08 (m, 2 H), 3.41 - 3.33 (m, 3 H). ¹³C NMR (DMSO- δ: 170.3, 139.1, 137.5, 128.9, 128.3, 128.2, 128.1, 127.7, 127.1, 126.8, 126.4, 59.0, 42.3.

Elemental Analysis : Calcd. C: 77.39; H: 6.49; N: 7.52.

Found: C: 77.08; H: 6.45; N: 7.33.

Standard-B

1H NMR (CDCk) δ : 7.50 (bs, IH), 7.38-7.25 (m, 2H), 7.19-7.03 (m, 3H), 6.78-6.61(m, 4H), 5.5 (bs, IH), 4.23(d, J = 12.1Hz, 2H), 3.98-3.76 (m, 16H), 3.26-3.54 (m, 2H), 3.51 (dt, J = 6.2,6.6, 2H), 2.75 (t, J = 5.9, 2H).

¹³C NMR (CDCh) δ : 153.99, 151.25, 149.13, 132.14, 131.99, 130.12, 129.90, 124.26, 122.05, 120.61, 115.56, 115.27, 111.93, 111.44, 107.63, 79.08, 61.27, 60.74, 57.72, 56.46, 56.01, 55.90, 55.83, 54.28, 41.02, 35.18.

Elemental Analysis: Calcd.: C: 64.97; H: 6.36; N: 5.05.

Found: C: 64.82; H: 6.43; N: 4.88

Standard-C:

1H NMR (CDCh) δ : 8.33 (d, J = 8.4Hz, IH), 7.87-7.79 (m, 2H), 7.62-7.35 (m, 7H),6.86 (d, J = 8.8 Hz, 2H), 5.5 (bs, 0.5 H), 4.9-4.6 (m, 2H), 4.02 (q, J = 7.0, 2H), 3.8-

3.4 (m, 4H), 3.25-3.05 (m, 2H), 1.61-1.45 (m, 4H), 1.40 (t, J = 7.0 Hz, 3H), 1.36-1.10

(m,2H).

¹³C NMR (CDCh) δ : 130.46, 128.86, 128.77, 128.67, 128.44, 128.30, 126.26, 125.73,

125.30, 124.46, 114.67, 83.07, 63.48, 59.71, 58.48, 53.59, 46.77, 43.43, 26.41, 25.57, 24.34, 14.77. Elemental Analysis: Calcd.: C: 75.65; H: 7.26; N: 6.30.

Found: C: 75.49; H: 7.10; N: 6.12. Standard-D:

1H NMR (CDCh) δ : 7.43 (bs, lH),7.36-7.24 (m, 5 H), 7.10(d, J = 4.4 Hz, IH), 5.35 (bs, IH), 4.15 (d, J = 11.0 Hz, 2H), 3.77 (bs, 0.5H), 3.42 (bs, IH), 3.33-3.12 (m, 4H), 1.46 (ddt, J = 6.0, 7.0 Hz, 2H), 1.30 (dq, J = 7.3, 2H), 0.91 (t, J = 7.3Hz, 3H). ¹³C NMR (CDCh) δ: 174.50, 140.12, 138.30, 134.34, 129.69, 129.24, 127.85, 127.27, 126.83, 125.56, 122.58, 79.52, 61.42, 58.27, 57.41, 39.41, 31.56, 19.98, 13.64. Elemental Analysis: Calcd.: C: 60.23; H: 6.12; N: 7.39

Found: C: 60.21; H: 6.04; N: 7.25.

Standard-E:

1H NMR (CDCh) δ: 8.31 (s, 1 H), 8.12 (d, J = 7.33 Hz, 1 H), 7.78 (d, J = 7.69 Hz, 1 H), 7.49 (t, J = 8.07 Hz, 1 H), 7.29 (d, / = 8.43 Hz, 2 H), 6.87 (d, J = 8.43 Hz, 2 H), 4.22 - 4.17 (m, 2 H), 4.01 (q, J = 6.96 Hz, 2 H), 3.44 - 3.39 (m, 6 H), 3.32 (s, 3 H), 3.18 - 3.13 (m, 1 H), 2.23 (s, 1 H), 1.40 (t, J = 6.96 Hz, 3 H).

¹³C NMR (CDCh) δ : 159.4, 148.5, 138.8, 135.3, 130.3, 129.5, 128.1, 124.1, 122.8, 114.9, 71.0, 63.7, 58.8, 58.7, 39.6, 14.9. Elemental Analysis: Calcd.: C: 61.53; H: 6.34; N: 9.78.

Found: C: 61.63; H: 6.33; N: 9.87.

_*

Analytical Methods:

Mass spectra, ¹³C NMR and 1H-NMR were obtained for compounds of Formula I synthesized using the process of the present invention. Mass spectra and 1H-NMR were obtained by conventional methods known to one skilled in the art. Elemental analysis was done using commercial services from Robertson Microlit Laboratories,

Inc.

DEFINITIONS

"Suitable solvent", as used herein is meant to indicate a solvent which is compatible with reaction conditions and able to swell the solid support (SS). Representative examples of suitable solvent are THF, dioxane, toluene, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), dichloro methane (DCM), N-methyl pyrrolidinone (NMP) or mixtures thereof. A list of suitable solvents can be found in Tet. Lett. 1998, 39, 8451-54, and is incorporated herein by reference. "Alkyl" or "alkyl radical", unless indicated otherwise, is meant to indicate a hydrocarbon moiety of up to 14 carbon atoms. This hydrocarbon is generally attached to at least one other atom, and can be straight chain, or branched, or cyclic.

The term "aryl" means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated. Thus a C₆-Cι₄ aryl group includes phenyl, naphthyl, anthracenyl, etc. The term "heteroaryl" means aryl, as defined above, wherein one or more of the carbon atoms is replaced by a hetero atom chosen from N, O, and S. The hetero atoms can exist in their chemically allowed oxidation states. Thus Sulfur (s) can exist as a sulfide, sulfoxide, or sulfone. Each heteroaryl ring comprises from five (5) to fourteen (14) atoms. Illustrative examples of heteroaryl groups are thienyl, furyl, pyrrolyl, indolyl, pyrimidinyl, isoxazolyl, purinyl, imidazolyl, pyridyl, pyrazolyl, quinolyl, and pyrazinyl.

The term "array of compounds" indicates a collection of independent

(individual) compounds that are synthesized by the process of the present invention. Generally the term library of compounds indicates a collection of individual compounds distinct from one another. Also included in the library of compounds is a mixture of the individual compounds.

The term "heterocyclyl" means a saturated or partially unsaturated cyclo alkyl group containing from 5 to 14 carbon atoms wherein one or more of the carbon atoms is replaced by a hetero atom chosen from N, O, and S. The hetero atoms can exist in their chemically allowed oxidation states. Thus Sulfur (S) can exist as a sulfide, sulfoxide, or sulfone. The heterocycloalkyl group can be completely saturated or partially unsaturated. Illustrative examples are piperidine, 1,4-dioxane, and morpholine. The term "group capable of forming a stable bond with a nitrogen atom" as used herein represents a substituent which is capable of forming a covalent bond with a nitrogen atom to form a primary or secondary amine group to form a compound of formula-6. Illustrative examples of such a substituent are optionally substituted alkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted alkoxy groups, l-(N,N-dimethyl)-prop-2-yl, 2-dimethylamino- 1 -methyl-ethyl, 3-pyrrolidin-l-yl-propyl, 2-morpholin-4-yl-ethyl, 2-(4-methyl- piperazin-l-yl)-ethyl, 4-diethylamino-l -methyl-butyl, 2-diethylamino-ethyl, 2- hydroxy-butyl, 3-methoxy-propyl, cyclohexyl, tetrahydro-furan-2-ylmethyl, benzyl, 2-amino benzyl, 2-fluoro benzyl, 2-oxo-azepan-3-yl, 2-(2-oxo- pyrrolidin-l-yl)-ethyl, 2-(3,4-dimethoxy-phenyl)-ethyl, 2-(3a,7a-dihydro-lH-indol- 3-yl)-ethyl, 2-hydroxy-cyclohexyl, l-benzyl-2-hydroxy-ethyl, 5-hydrox y- 1,3,3- trimethyl-cyclohexylmethyl, 4-methyl -benzyl, 2-amino-3-fluoro-benzyl, 3- hydroxy-2,2-dimethyl-propyl, 2-(2-hydroxy-ethoxy)-ethyl, and 2-hydroxy-ethyl. A comprehensive list of amines substituted with suitable substituent(s) can be found in the Aldrich Chemicals catalog, which is incorporated herein by reference.

The term "substituted" indicates that the group is substituted with one or more substituents selected from a group consisting of aryl, OCF₃, halogen, S-haloalkyl, S- haloaryl, NHC_1-4-CN, N(C_1-4-CN)₂, O-C(O)-C_1-4 alkyl, C_1-10 alkyl, nitro, thio-alkyl, cyano and C_1-4 alkoxy.

The term "solid support" (SS), as used in the present invention, signifies polymeric material for supported synthesis. A detailed description of the terms linker molecule and solid support can be found in The Combinatorial Index, B. A. Bunin, Academic Press (1998), which is incorporated herein by reference. The term "inert medium" or "inert solvent" is intended to represent solvents which do not react with the reagents dissolved therein. Illustrative examples of inert solvents are tetrahydrofuran (THF), methylene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), dioxane, chloroform, and DMSO.

The term "halogen" represents Cl, I, Br or F. The term "base" as used herein represents a tertiary amine. Illustrative examples are trialkyl amines, pyridine and lutidine. The term "protonating agent" as used herein represents a chemical agent which is capable of donating a hydrogen (proton) atom to a hetero atom like nitrogen. Illustrative examples of protonating agents are trifluoro acetic acid (TFA), hydrochloric acid (HC1), p-toluene sulfonic acid and methane sulfonic acid.

Abbreviations:

DMF: dimethyl formamide

DCM: dichloromethane

TMS; trimethyl silyl

MeOH: methanol

DMAP: dimethyl aminopyridine

DIC: diisopropylcarbodiimide

DIPEA: diisopropyl ethyl amine

DMSO: dimethyl sulfoxide

Claims

A process for synthesizing a compound or an array of compounds of Formula I

.Formula I

wherein

R¹ is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; R² is selected from (CH₂)_0-6 aryl, (CH₂)o_-6 substituted aryl, Cι-C₄ alkyl, (CH₂)o-₆ heteroaryl and (CH₂)o_-6 heterocyclyl;

R⁵ is selected from H, COOR¹⁰, CO-alkyl, CON(R¹⁰)₂ and CO-aryl ;

R⁶ is selected from H, aryl, Cι„ alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH₂)j_-4 aryl;

.formula-2

with a compound of formula-3

.formula-3

where R , R , R and R are defined above, and SS represents a solid support, to form a compound or an array of compounds of formula-4

.formula-4

where R¹, R², R⁵, R⁶ and SS are as defined above;

(ii) treating a compound or an array of compounds of formula-4 in succession with

(a) a solution of a protonating agent in an inert medium; and

(b) an inert solvent solution of an alkylating agent, to form a compound or an array of compounds of formula 5,

.formula 5

where R¹, R², R⁵, R⁶ and SS are as defined above, and ALKYL represents methyl, CH₂-TMS or CH₂-CN; (iii) treating, in an inert medium and in the presence of a base, a compound or an array of compounds of formula 5 with an amine of formula 6

R³R⁴NH formula 6 where R³ and R⁴ are as defined above, to form a compound or an array of compounds of Formula I.

2. A process of Claim 1 where R¹ is selected from H, Cj_-6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, C_1-4 alkoxy, phenyl, Cι_-4 alkyl and C_3-8 branched alkyl; heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from

R² is selected from

(CH₂)_1-3 aryl,

Cι_-4 alkyl,

(CH₂)_1-3 heteroaryl, and (CH₂)_1-3 substituted aryl, said aryl substituted with one to five substituents selected from OC_1-3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO₂, C_1-4 alkyl, phenyl,

SC_1-4 alkyl, NH₂, NHC_1-4 alkyl, N(C alkyl)₂ and CF₃;

2-dimethylamino- 1 -methyl-ethyl,

3-pyrrolidin- 1 -yl-propyl,

2-morpholin-4-yl-ethyl,

2-(4-methyl-piperazin-l-yl)-ethyl, 4-diethylamino-l-methyl-butyl,

2-diethylamino-ethyl,

2-hydroxy-butyl,

3 -methox y-propyl , cyclohexyl, tetrahydro-furan-2-ylmethyl, benzyl,

2-amino benzyl,

2-fluoro benzyl,

2-oxo-azepan-3-yl, 2-(2-oxo-pyrrolidin-l-yl)-ethyl,

2-(3,4-dimethoxy-phenyl)-ethyl,

2-(3a,7a-dihydro-lH-indol-3-yl)-ethyl,

4-methyl-benzyl,

2-amino-3 -fluoro-benzyl ,

3-hydroxy-2,2-dimethyl-propyl,

2-(2-hydroxy-ethoxy)-ethyl, and 2-hydroxy-ethyl;

R⁵ is selected from H, COOH, COC₂H₅, CO-aryl and COCH₃; and

R⁶ is selected from H, Ph, CH₃, C₂H₅, aryl, CF₃ and benzyl.

3. A process of Claim 2 wherein step(i) is carried out in a suitable solvent selected from DMF, DMSO, toluene, DMA, THF, DCM and NMP, at a temperature of from about 40°C to about 120°C.

4. A process of Claim 3 wherein step (i) is carried out in a suitable solvent selected from DMF, DMSO and toluene, at a temperature of from about 70°C to about 100°C.

5. A process of Claim 4 wherein step (iii) is carried out in the presence of a base selected from pyridine, triethyl amine, lutidine, trimethyl amine or excess of an amine of formula-6.

6. An array of compounds of Formula I

Formula I

wherein

R¹ is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; R² is selected from (CH₂)o_-6 aryl, (CH₂)_0-6 substituted aryl, C]-C₄ alkyl, (CH₂)o-₆ heteroaryl and (CH₂)o_-6 heterocyclyl;

R⁵ is selected from H, COOR¹⁰, CO-alkyl, CON(R¹⁰)₂ and CO-aryl ;

R⁶ is selected from H, aryl, C_1- alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH₂)_1-4 aryl; and R independently at each occurance represents C_1-4 alkyl, aryl, H or heterocyclyl.

7. An array of compounds of Claim 6, wherein

R¹ is selected from H, C_1-6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, C_1-4 alkoxy, phenyl, C_1-4 alkyl, C_3-8 branched alkyl and CN, heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from

R is selected from

(CH₂)_1-3 aryl,

Cι- alkyl,

(CH₂)_1-3 heteroaryl, and

SC_1-4 alkyl, NH₂, NHC_1-4 alkyl, N(C_1-4 alkyl)₂ and CF₃;

R³ and R⁴ are independently selected from H, C_1-6 alkyl,

1 -(N,N-dimethyl)-prop-2-yl,

2-dimethylamino- 1 -methyl-ethyl,

3-pyrrolidin- 1 -yl-propyl,

2-morpholin-4-yl-ethyl,

2-(4-methyl-piperazin- 1 -yl)-ethyl,

4-diethylamino-l-methyl-butyl,

2-diethylamino-ethyl,

2-hydroxy-butyl,

3-methoxy-propyl, cyclohexyl, tetrahydro-furan-2-ylmethyl, benzyl,

2-amino benzyl,

2-fluoro benzyl,

2-oxo-azepan-3-yl, 2-(2-oxo-pyrrolidin-l-yl)-ethyl,

2-(3 ,4-dimethoxy-phenyl)-ethyl,

2-(3a,7a-dihydro-lH-indol-3-yl)-ethyl,

4-methyl-benzyl,

2-amino-3-fluoro-benzyl,

3-hydroxy-2,2-dimethyl-propyl,

2-(2-hydroxy-ethoxy)-ethyl, and 2-hydroxy-ethyl;

R⁵ is selected from H, COOH, COC₂H₅, CO-aryl and COCH₃; and

R⁶ is selected from H, Ph, CH₃, C₂H₅, aryl, CF₃ and benzyl.

8. A process for synthesizing a compound or an array of compounds of formula-4

.formula-4

wherein

R¹ is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; R² is selected from (CH₂)₀.₆ aryl, (CH₂)_0-6 substituted aryl, C C alkyl, (CH₂)_0-6 heteroaryl and (CH₂)o_-6 heterocyclyl;

R⁵ is selected from H, COOR¹⁰, CO-alkyl, CON(R¹⁰)₂ and CO-aryl ;

R⁶ is selected from H, aryl, C_1-4 alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH₂)_1-4 aryl;

R¹⁰ independently at each occurance represents C_1-4 alkyl, aryl, H or heterocyclyl; and

.formula-2

with a compound of formula-3

.formula-3

where R , R , R and R are defined above, and SS represents a solid support, to form a compound or an array of compounds of formula-4, where R¹, R², R⁵, R⁶ and

SS are as defined above.

9. A process of Claim 8

R¹ is selected from H, C_1-6 alkyl, Ph, naphthyl, phenyl substituted with one to three substituents selected from halogen, nitro, Cι_-4 alkoxy, phenyl, Cμ₄ alkyl, C_3-8 branched alkyl and CN, heteroaryl selected from thiophene, furan, imidazole, nitro furan, oxazole and pyridyl, and heterocyclyl selected from

R² is selected from (CH₂)ι-3 aryl,

CM alkyl,

(CH₂)_1-3 heteroaryl, and

(CH₂)_1-3 substituted aryl, said aryl substituted with one to five substituents selected from OC_1-3 alkyl, O-phenyl, halogen, COOH, OH, CN, NO₂, C_1-4 alkyl, phenyl, SC_M alkyl, NH₂, NHC_1-4 alkyl, N(C_1-4 alkyl)₂ and CF₃;

2-dimethylamino-l-methyl-ethyl,

3-pyrrolidin-l-yl-propyl, 2-morpholin-4-yl-ethyl,

2-(4-methyl-piperazin-l-yl)-ethyl,

4-diethylamino- 1 -methyl -butyl,

2-diethylamino-ethyl ,

2-amino benzyl, 2-fluoro benzyl, 2-oxo-azepan-3-yl,

2-(2-oxo-pyrrolidin-l-yl)-ethyl,

2-(3,4-dimethoxy-phenyl)-ethyl,

2-(3a,7a-dihydro-lH-indol-3-yl)-ethyl,

2-hydroxy-cyclohexyl,

1 -benzyl-2-hydroxy-ethyl,

5-hydroxy-l,3,3-trimethyl-cyclohexylmethyl,

4-methyl-benzyl,

2-amino-3-fluoro-benzyl,

3-hydroxy-2,2-dimethyl-propyl,

2-(2-hydroxy-ethoxy)-ethyl, and

2-hydroxy-ethyl; -

R⁵ is selected from H, COOH, COOCH₃ and COCH₃; and

R⁶ is selected from H, Ph, CH₃, C₂H₅, aryl, CF₃ and benzyl.

10. A process of Claim 9 wherein step(i) is carried out in an inert medium selected from DMF, DMSO, toluene, DMA, THF, DCM and NMM, at a temperature of from about 40°C to about 120°C.

11. A process of Claim 10 wherein step (i) is carried out in an inert medium selected from DMF, DMSO and toluene, at a temperature of from about 70°C to about 100°C.

12. A compound or an array of compounds of formula-4

.formula-4 wherein

R¹ is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl; R² is selected from (CH₂)_0-6 aryl, (CH₂)₀.₆ substituted aryl, C1-C4 alkyl, (CH₂)o_-6 heteroaryl and (CH₂)_0-6 heterocyclyl;

R⁵ is selected from H, COOR¹⁰, CO-alkyl, CON(R¹⁰)₂ and CO-aryl ; R⁶ is selected from H, aryl, C_1-4 alkyl, CN, substituted aryl, heteroaryl, substituted heteroaryl, CF₃ and (CH₂)_1-4 aryl;

R¹⁰ independently at each occurance represents Cι_-4 alkyl, aryl, H or heterocyclyl; and SS represents a solid support.