IP Library Granted Patent US 9,447,101
Granted Patent B2
US 9,447,101 · App. 14/403,014 · Granted Sep 20, 2016

Pyrrolo[2,1-

Inventors: Chunhao Yang (Shanghai, CN); Linghua Meng (Shanghai, CN); Yanhong Chen (Shanghai, CN); Xiang Wang (Shanghai, CN); Cun Tan (Shanghai, CN); Jiapeng Li (Shanghai, CN); Jian Ding (Shanghai, CN); Yi Chen (Shanghai, CN)
Assignees: Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Shanghai Haihe Pharmaceutical Co., Ltd.
C07D487/04A61K31/5377A61K31/5386C07D498/08C07D519/00
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Quick Facts
Patent No.
US 9,447,101
App. No.
14/403,014
Granted
Sep 20, 2016
Kind
B2
Abstract

The present invention relates to a pyrrolo[2,1-f][1,2,4]triazine compound, an isomer thereof or a pharmaceutically acceptable salt, ester or hydrate thereof, and a preparation method and application thereof. The pyrrolo[2,1-f][1,2,4]triazine compound has a structure expressed in general formula (I). The pyrrolo[2,1-f][1,2,4]triazine compound expressed in general formula (I) can inhibit a phosphatidylinositol-3 kinase (PI3K) signal pathway, thereby being used to prepare medicine for treating phosphatidylinositol-3 kinase related diseases such as cancer.

Claims (46)

1. A pyrrolo[2,1-f][1,2,4]triazine compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof,

wherein,

X═CH or N;

R 1 is —NR 5 R 6 ;

R 2 is

R 3 is —NH 2 , —NHC(O)NHR 11 , —NHC(O)OR 11 , —NHC(O)R 11 , —CH 2 OH, —CH 2 S(O) 2 R 12 or —CH 2 NHS(O) 2 R 12 ;

R 4 is H or CF 3 ;

R 5 and R 6 are each independently a C1-C4 alkyl, or combined with the nitrogen atom to which they are attached to form an unsubstituted 5-8 membered saturated heterocycle or a 5-8 membered saturated heterocycle substituted by a substituent, the substituent is —S(O) 2 R 12 ;

R 7 , R 8 , R 9 and R 10 are each independently H or a C1-C3 alkyl, alternatively, R 7 and R 8 , or R 9 and R 10 , with the carbon atoms to which they are attached as bridge carbon atoms, form bridged bicylco-heterocycle with morpholine ring;

R 11 is a C1-C4 alkyl, an unsubstituted C3-C6 cycloalkyl or a C3-C6 cycloalkyl substituted by one or more substituents, an unsubstituted benzyl or a benzyl substituted by one or more substituents, an unsubstituted phenyl or a phenyl substituted by one or more substituents, an unsubstituted isoxazolyl or an isoxazolyl substituted by one or more substituents, or an unsubstituted pyridyl or a pyridyl substituted by one or more substituents, and the one or more substituents are selected from halogen, a C1-C3 alkyl, or a C1-C3 alkoxyl, —CF 3 , —C(O)OR 12 , —C(O)NR 12 R 15 ,

R 12 and R 15 are each independently a C1-C3 alkyl.

2. The pyrrolo[2,1-f][1,2,4]triazine compound, or the pharmaceutically acceptable salt or hydrate thereof of claim 1 , wherein the compound has the following structure shown in formula A or formula B:

3. The pyrrolo[2,1-f][1,2,4]triazine compound, or the pharmaceutically acceptable salt or hydrate thereof of claim 1 , wherein,

R 2 is

R 5 and R 6 are combined with the nitrogen atom to which they are attached to form an unsubstituted saturated heterocycle or a saturated heterocycle substituted by a substituent, wherein the saturated heterocycle is pyrrolidyl, piperidinyl or piperazinyl, and the substituent is —S(O) 2 R 12 .

4. The pyrrolo[2,1-f][1,2,4]triazine compound, or the pharmaceutically acceptable salt or hydrate thereof of claim 3 , wherein,

R 1 is dimethylamino or 1-methylsulfonyl piperazinyl;

R 2 is

R 11 is a methyl, an ethyl, a propyl, a cyclopropyl, a tert-butyl, an iso-butyl, a 4-fluorobenzyl, an unsubstituted phenyl or a phenyl substituted by one or more substituents, an unsubstituted isoxazolyl or an isoxazolyl substituted by one or more substituents, or an unsubstituted pyridine ring or a pyridine ring substituted by one or more substituents, and the substituent is selected from the group consisting of a fluorine, a chlorine, a trifluoromethyl, a methyl, a methoxy, an ethoxycarbonyl, a dimethylaminocarbonyl, a 4-methyl-piperazine-1-carbonyl, a piperidine-1-carbonyl and a 4-dimethylamino-piperidine-1-carbonyl.

5. The pyrrolo[2,1-f][1,2,4]triazine compound, or the pharmaceutically acceptable salt or hydrate thereof of claim 1 , wherein the compound has the following structure of formula:

wherein, R 1 , R 2 , R 11 and R 12 are defined as in claim 1 , and

R 16 and R 17 are identical or different, and each is independently selected from a C1-C4 alkyl, or R 16 and R 17 are combined with the nitrogen atom to which they are attached to form a 4-methyl-piperazinyl, a 4-dimethylamino-piperidinyl or piperidin-1-yl.

6. The pyrrolo[2,1-f][1,2,4]triazine compound, or the pharmaceutically acceptable salt or hydrate thereof of claim 1 , wherein the compound has the following structure of formula:

7. A preparation method for the pyrrolo[2,1-f][1,2,4]triazine compounds of claim 1 , comprising the following steps:

wherein, R 13 is a nitro or —CH 2 OAc; R 14 is an amino or —CH 2 OH;

1) pyrrole derivative 1 and chloramine in anhydrous N,N-dimethylformamide are subjected to N-amination reaction in the presence of a base to obtain compound 2;

2) the compound represented by Formula 2 without being purified is subjected to ammonolysis to give compound 3;

3) compound 3 reacts with an aromatic aldehyde under the action of metal Lewis acid to give compound IIa, or compound 3 and an aldehyde, under catalysis by Lewis acid such as a solution of boron trifluoride in diethyl ether, are subjected to condensation to give a Schiff base, and then to oxidative cyclization to give compound IIa;

4) compound IIa is subjected to chlorination reaction in the presence of a base to give compound IIb;

5) compound IIb and R 2 —H are subjected to nucleophilic substitution reaction to give compound IIc;

6) the ester group of compound IIc is subjected to hydrolysis reaction; or the nitro group of compound IIc is subjected to reduction reaction, and then the ester group of compound IIc is hydrolyzed;

7) compound IId reacts with a R 1 —H amine or a substituted or unsubstituted 3-8 membered saturated heterocycle containing at least one nitrogen atom to give compound I′, and the substituent is —S(O) 2 R 12 ;

8) compound IIe is reduced by a reducing agent to give compound I′; and

9) compound I′ is further subjected to addition reaction with R 11 NCO, to esterification reaction or amidation reaction with R 11 OC(O)Cl, to esterification reaction or amidation reaction with R 11 C(O)OH or R 11 C(O)Cl, or to esterification reaction or amidation reaction with R 12 S(O) 2 Cl thereby converting R 14 in compound I′ into R 3 and forming the compounds represented by the formula I.

8. The preparation method of claim 7 , wherein,

the base in step 1) is sodium hydride, potassium carbonate or potassium tert-butoxide;

the metal Lewis acid in step 3) can be a monovalent or divalent copper reagent, and the reaction temperature is 80-150° C.;

the chlorination agent in step 4) is phosphorus oxychloride or phosphorus pentachloride, and the base used is N,N-dimethylaniline or 4-dimethylaminopyridine;

the amine in step 7) is dimethylamine or 1-methylsulfonyl piperazine; and

the reducing agent in step 8) is borane-tetrahydrofuran complex or borane-dimethyl sulfide complex.

9. The preparation method of claim 8 , wherein,

the copper reagent is cuprous bromide, cuprous chloride, copper acetate monohydrate, copper bromide, anhydrous copper chloride, or copper chloride dihydrate; and the reaction solvent is dimethyl sulfoxide or N,N-dimethylformamide, N,N-dimethylacetamide.

10. A method for inhibiting phosphatidylinositol 3-kinase in cancer cells, the method comprising administering to a subject in need thereof a pyrrolo[2,1-f][1,2,4]triazine compound of claim 1 , wherein the subject is a human patient having a cancer selected from the group consisting of human rhabdomyosarcoma, non-small cell lung cancer, human glioma, prostate cancer, ovarian cancer, liver cancer, colon cancer, and breast cancer.

11. The pyrrolo[2,1-f][1,2,4]triazine compound, or the pharmaceutically acceptable salt or hydrate thereof of claim 2 , wherein,

R 2 is

R 5 and R 6 are combined with the nitrogen atom to which they are attached to form an unsubstituted saturated heterocycle or a saturated heterocycle substituted by a substituent, wherein the saturated heterocycle is pyrrolidyl, piperidinyl or piperazinyl, and the substituent is —S(O) 2 R 12 .

Assignments (4)
CHANGE OF NAME Recorded Oct 22, 2024
From: SHANGHAI HAIHE PHARMACEUTICAL CO., LTD.
To: HAIHE BIOPHARMA CO., LTD.
Reel/Frame 069197/0001 →
CHANGE OF ADDRESS Recorded Oct 22, 2024
From: HAIHE BIOPHARMA CO., LTD.
To: HAIHE BIOPHARMA CO., LTD.
Reel/Frame 069197/0147 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 22, 2024
From: SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES
To: HAIHE BIOPHARMA CO., LTD.
Reel/Frame 068962/0027 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 26, 2015
From: YANG, CHUNHAO; MENG, LINGHUA; CHEN, YANHONG; WANG, XIANG; TAN, CUN; LI, JIAPENG; DING, JIAN; CHEN, YI
To: SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES; SHANGHAI HAIHE PHARMACEUTICAL CO., LTD.
Reel/Frame 035032/0459 →
Priority Claims (1)
CN 2012 1 0177980 · May 31, 2012 · national
Continuity (1)
Related Publication 20150141644A1 · May 21, 2015