KR20150002952A - Pharmaceutical composition for preventing and treating metabolic bone diseases which comprises pyridopyrimidine derivatives - Google Patents

Pharmaceutical composition for preventing and treating metabolic bone diseases which comprises pyridopyrimidine derivatives Download PDF

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KR20150002952A
KR20150002952A KR1020130074660A KR20130074660A KR20150002952A KR 20150002952 A KR20150002952 A KR 20150002952A KR 1020130074660 A KR1020130074660 A KR 1020130074660A KR 20130074660 A KR20130074660 A KR 20130074660A KR 20150002952 A KR20150002952 A KR 20150002952A
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compound
hydrochloride
pyrido
bromo
pyrimidin
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KR1020130074660A
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Korean (ko)
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김세원
김중호
김세년
강대필
정동식
박성호
이상엽
박송은
오주현
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주식회사 오스코텍
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

Since the pyridopyrimidine derivative-containing pharmaceutical composition of the present invention promotes differentiation of osteoblast to increase bone mass and bone density, it can be used not only for prevention and treatment of metabolic bone diseases such as osteoporosis, but also for bone formation during growing period. In addition, the pharmaceutical composition of the present invention can be used as a therapeutic agent for various metabolic bone diseases such as nephrotic syndrome, osteomalacia, Paget's disease, osteogenesis imperfecta, and can also be used as a therapeutic agent for the treatment of fracture and bone cancer metastasis have.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition for preventing and treating metabolic bone diseases containing a pyridopyrimidine derivative,

The present invention relates to a pharmaceutical composition for preventing and treating metabolic bone diseases containing pyridopyrimidine derivatives as an active ingredient.

Human bone grows up to the early 30s, when bone growth ends, to form the maximal bone mass, and then bone remodeling, a process in which some bones are resorbed and formed (bone formation) And maintain a healthy state. Bone formation is carried out by osteoblasts, and bone uptake by osteoclasts. The activity of these two cells is balanced so that healthy bones can be maintained.

Osteoporosis is a disease in which the bone mass, which determines the physical strength of the bony tissue, is reduced for various reasons, and the bone quality is widened. In the case of osteoporosis, the bone is weakened and the fracture easily occurs in the femur and vertebrae, which limits the long-term activity and adversely affects the health. For this reason, it is known that osteoporosis accounts for 15% of the causes of death in the elderly. Bone mass is affected by several factors including genetic factors, nutritional intake, changes in hormones, and differences in exercise and lifestyle habits. The causes of osteoporosis include age, lack of exercise, low birth weight, hormone abnormality, smoking, low calcium diet, menopause, and ovarian resection. Especially, in women, the bone mineral density is continuously decreased after 30 years of age, and estrogen, which is a hormone, decreases rapidly after menopause, thereby increasing the activity of osteoclasts and decreasing bone density.

Presently available osteoporosis medicines include bisphosphonate, hormone, vitamin D, calcitonin and calcium preparations. Of these, bisphosphonates are the largest share in the osteoporosis drug market. They are the most widely used in the market for osteoporosis drugs, and are currently marketed or under clinical trials such as alendronate (Merck), risedronate (Warner-in-Chess), zoledronate (Novartis) Nate (Hoffman Roxas) and minodronate (Yamanouchi).

Bisphosphonate preparations that are taken orally have poor water uptake and are difficult to take and often cause esophagitis. Calcitonin preparations and parathyroid hormone preparations are expensive and can not be administered orally. Calcium preparations have few side effects, but are limited to preventive effects rather than treatments. In addition, most of the currently used osteoporosis therapeutic agents have an effect of inhibiting bone loss, and thus can not restore bone that has already been lost. Patients with osteoporotic osteoporosis who has osteoporotic effect have to be injected directly every day, expensive and have not been used extensively because of the disadvantage of no clinical trial results of more than 2 years.

There is a high demand for the development of a bone formation promoter having an effect of restoring a bone that has already been lost due to the problem of the existing osteoporosis therapeutic agent. In addition, the osteogenesis promoter can be used not only for osteoporosis including osteoporosis but also for various metabolic bone diseases such as nephritic bone turnover, osteomalacia, Paget's disease and osteoporosis, and it can be used for treatment of fracture, It can be used as a remedy.

It is an object of the present invention to provide a pharmaceutical composition for the treatment or prevention of metabolic bone diseases comprising pyridopyrimidine derivatives which exhibit excellent efficacy and low side effects.

According to the above object, the present invention provides a pharmaceutical composition for preventing or treating metabolic bone diseases, which comprises a pyridopyrimidine derivative represented by the following formula (1), a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient :

Figure pat00001

In this formula,

R 1 is C 3-6 cycloalkylamino, piperazinyl, NC 1-3 alkylpiperazinyl, pyrrolidinyl, aminopyrrolidinyl, di C 1-3 alkylaminopyrrolidinyl, piperidinyl, aminopiper NC 1-3 alkylpiperidinyl, NC 1-3 alkylpiperidinylamino, or (NC 1-3 alkylpiperidinyl) (C 1-3 alkyl) amino;

R 2 is halogen, optionally substituted with one or more halogen C 1-4 alkyl, optionally substituted with one or more halogen C 1 - 4 alkoxy, C 5 - 6 cycloalkyl, C 5 - 6 cycloalkyloxy, C 5 - 6 cycloalkyl methyloxy, C 6 - 12 aryl, C 6 - 12 aryloxy, C 6 - 12 aryl C 1 - 3 alkyloxy, methanesulfonyl, methoxycarbonyl, hydroxy carbonyl, C 6 - 12 aryl-carbonyl and C 6-12 having at least one substituent selected from the group consisting of heteroaryl, 5-6 membered aryl (wherein the C 6-12 aryl, C 6-12 aryloxy and C 6-12 aryl C 1-3 alkyloxy may each independently be substituted with one or more halogens or methyl, and said heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O and S; Indenyl, unsubstituted or substituted with hydrogen; Benzofuryl substituted or unsubstituted with hydrogen; Or naphthalenyl which is unsubstituted or substituted by hydrogen;

R 3 is hydrogen, chlorine, bromine, or iodine.

Since the pyridopyrimidine derivative-containing pharmaceutical composition of the present invention promotes differentiation of osteoblast to increase bone mass and bone density, it can be used not only for prevention and treatment of metabolic bone diseases such as osteoporosis, but also for bone formation during growing period. In addition, the pharmaceutical composition of the present invention can be used as a therapeutic agent for various metabolic bone diseases such as nephrotic syndrome, osteomalacia, Paget's disease, osteogenesis imperfecta, and can also be used as a therapeutic agent for the treatment of fracture and bone cancer metastasis have.

Hereinafter, the present invention will be described in more detail.

The pyridopyrimidine derivative contained in the pharmaceutical composition of the present invention has the structure of Formula 1 above. The pyridopyrimidine derivatives represented by the above formula (1) have been reported as inhibitors against various kinases including FLT3 in U.S. Patent Nos. 8,404,677 and WO2011 / 053861.

In Formula 1, R 1 is preferably NC 1-3 alkylpiperazinyl, di C 1-3 alkylaminopyrrolidinyl, aminopiperidinyl, or NC 1-3 alkylpiperidinyl, more preferably Is N-methylpiperazinyl, dimethylaminopyrrolidinyl, 4-aminopiperidinyl, or N-methylpiperidin-4-yl.

R 2 is preferably selected from the group consisting of halogen, C 1-4 alkoxy, trifluoromethoxy, C 5-6 cycloalkyloxy , C 5-6 cycloalkylmethyloxy, C 6-12 aryloxy and methanesulfonyl And more preferably C 6-12 aryl having at least one substituent selected from the group consisting of 4-trifluoromethoxyphenyl, 4-phenoxyphenyl, 4-cyclopentoxyphenyl, or 4-methanesulfonylphenyl.

Also, R < 3 > is preferably chlorine or bromine.

The structures of the compounds included in the scope of the present invention and their alkaline phosphatase (ALP) activity data (EC 50 , nM) are shown in Table 1 below.

Figure pat00002

Figure pat00003
Figure pat00004

Figure pat00005

Figure pat00006

Figure pat00007

Figure pat00008

Among them, examples of the specific compounds used in the present invention include the following, including pharmaceutically acceptable salts, hydrates, or solvates thereof:

1) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- phenoxyphenylamino) pyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 01)

2) Synthesis of (S) -methyl 4- (2- (3-aminopyrrolidin-1 -yl) -8-bromo-5-oxo-5,6-dihydropyrido [4,3- Methyl-benzoate hydrochloride (Compound No. 02)

3) Preparation of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (methylsulfonyl) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 03)

4) 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- isopropoxyphenylamino) pyrido [ Hydrochloride (Compound No. 04)

5) (R) -2- (3-Aminopyrrolidin-1-yl) -8-bromo-4- (4-isopropoxyphenylamino) pyrido [ 5 (6H) -one hydrochloride (Compound No. 05)

6) Synthesis of (S) -2- (3-aminopyrrolidin-1 -yl) -8-bromo-4- (4-isopropoxyphenylamino) pyrido [ 5 (6H) -one hydrochloride (Compound No. 06)

7) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (1, 3-difluoropropane-2-yloxy) phenylamino) pyrido [ 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 07)

8) (S) -2- (3-Aminopyrrolidin-1-yl) -8-bromo-4- (1,3- difluoropropan-2-yloxy) phenylamino) pyrido [ , 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 08)

9) Preparation of 2- (4-aminopiperidin-1-yl) -8-chloro-4- (4- (1, 3-difluoropropan-2-yloxy) phenylamino) pyrido [ 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 09)

10) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (2,3- dihydrobenzofuran- 5 -ylamino) pyrido [4,3- d] pyrimidine -5 (6H) -one hydrochloride (Compound No. 10)

11) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (5,6,7,8-tetrahydronaphthalen- ] Pyrimidin-5 (6H) -one hydrochloride (Compound No. 11)

Pyrido [4,3-d] pyrimidin-5 (6H) - (1-methylpiperidin- One (Compound No. 12)

13) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (oxazol- 6H) -one (Compound No. 13)

Pyrimidin-5 (6H) - (2-methylpiperidin-4-ylamino) pyrido [ (Compound No. 14)

Pyrimidin-2-ylmethyl) -pyrido [4,3-d] pyrimidin-4- Pyrimidin-5 (6H) -one (Compound No. 15)

16) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (4- phenoxyphenylamino) pyrido [ Hydrochloride (Compound No. 16)

17) 8-Bromo-4- (4- (cyclohexyloxy) phenylamino) -2- (1 -methylpiperidin- (6H) -one (Compound No. 17)

18) A mixture of 8-bromo-4- (4- (cyclohexylmethoxy) phenylamino) -2- (1 -methylpiperidin- (6H) -one (Compound No. 18)

19) 8-Chloro-4- (4- (cyclohexyloxy) phenylamino) -2- (1 -methylpiperidin- 6H) -one (Compound No. 19)

20) 8-Bromo-4- (4- (cyclopentylmethoxy) phenylamino) -2- (1 -methylpiperidin-4-ylamino) pyrido [4,3-d] pyrimidin- (6H) -one hydrochloride (Compound No. 20)

21) A mixture of 8-bromo-4- (4- (cyclopentyloxy) phenylamino) -2- (1 -methylpiperidin- 6H) -one hydrochloride (Compound No. 21)

D) pyrimidin-5 (6H) -one. ≪ / RTI > -One hydrochloride (Compound No. 22)

23) 8-Bromo-4- (2'-methyldiphenyl-4-ylamino) -2- (1- methylpiperidin- 5 (6H) -one hydrochloride (Compound No. 23)

24) 8-Bromo-4- (4-isopropyl-3-methylphenylamino) -2- (1- methylpiperidin- 6H) -one hydrochloride (Compound No. 24)

25) 8-Bromo-4- (4-tert-butylphenylamino) -2- (1- methylpiperidin- -One hydrochloride (Compound No. 25)

26) A mixture of 8-bromo-4- (4- (3,4-difluorophenoxy) phenylamino) -2- (1- methylpiperidin- ] Pyrimidin-5 (6H) -one hydrochloride (Compound No. 26)

Pyrido [4,3-d] pyrimidin-5 (6H) -quinolin-2- -One hydrochloride (Compound No. 27)

28) A mixture of 8-bromo-4- (4- (3,5-difluorophenoxy) phenylamino) -2- (1-methylpiperidin- ] Pyrimidin-5 (6H) -one (Compound No. 28)

29) 8-Bromo-4- (3-fluoro-4-phenoxyphenylamino) -2- (1 -methylpiperidin- 5 (6H) -one hydrochloride (Compound No. 29)

Pyrido [4,3-d] pyrimidin-5 (6H) - (4-fluorophenyl) Hydrochloride (Compound No. 30)

31) (R) -6- (3-Aminopyrrolidin-1-yl) -4-iodo-8- (4- (trifluoromethyl) phenylamino) isoquinolin- Hydrochloride (Compound No. 31)

32) (S) -6- (3-Aminopyrrolidin-1-yl) -4-bromo-8- (4- (trifluoromethyl) phenylamino) isoquinolin- Hydrochloride (Compound No. 32)

Pyrimidin-5 (6H) -one < / RTI > Hydrochloride (Compound No. 33)

34) (R) -2- (3-Dimethylamino) pyrrolidin-1-yl) -8-iodo-4- (4- phenoxyphenylamino) pyrido [ 5 (6H) -one (Compound No. 34)

Pyrido [4,3-d] pyrimidin-2-one (35 mg) was obtained as colorless crystals from 2- (4-aminopiperidin- Pyrimidin-5 (6H) -one hydrochloride (Compound No. 35)

Pyrido [4,3-d] pyrimidin-2-one (36 mg) as a colorless oil. Pyrimidin-5 (6H) -one (Compound No. 36)

37) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- methoxy- 3- methylphenylamino) pyrido [4,3- d] pyrimidin- ) -One hydrochloride (Compound No. 37)

38) Methyl 4- (2- (4-aminopiperidin-1 -yl) -8-bromo-5-oxo-5,6-dihydropyrido [4,3- d] pyrimidin- 6H) -one hydrochloride (Compound No. 38)

39) 2- (4-Aminopiperidin-l-yl) -8-bromo-4- (4- (4- fluorophenoxy) phenylamino) pyrido [ 5 (6H) -one hydrochloride (Compound No. 39)

40) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (3,4- difluorophenoxy) phenylamino) pyrido [ Pyrimidin-5 (6H) -one hydrochloride (Compound No. 40)

41) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (trifluoromethoxy) phenylamino) pyrido [ 6H) -one hydrochloride (Compound No. 41)

42) A mixture of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (3,4-fluorophenoxy) phenylamino) pyrido [ Methyl-5- (6H) -one hydrochloride (Compound No. 42)

43) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (3- isopropylphenylamino) pyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 43)

44) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (cyclopentyloxy) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 44)

45) Methyl 3- (2- (4-aminopiperidin-1-yl) -8-bromo-5-oxo-5,6-dihydropyrido [4,3- d] pyrimidin- 6H) -one hydrochloride (Compound No. 45)

4- (2,3-dihydrobenzofuran-5-ylamino) -2- (piperazin-1 -yl) pyrido [4,3- d] pyrimidin- ) -One hydrochloride (Compound No. 46)

Pyrimido-5 (6H) -quinolinone < / RTI > -One (Compound No. 47)

48) 2- (4-Aminopiperidin-1-yl) -4- (4-benzooxyl) phenylamino) -8-bromopyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 48)

49) 8-Bromo-4- (2,3-dihydro-1H-inden-5-ylamino) -2- (1 -methylpiperidin- ] Pyrimidin-5 (6H) -one (Compound No. 49)

2- (Piperazin-1 -yl) pyrido [4,3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 50)

51) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (2,3-dihydro- Yl) pyrido [4,3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 51)

52) A mixture of 8-chloro-4- (4- (cyclopentyloxy) phenylamino) -2- (1-methylpiperidin- ) -One (Compound No. 52)

Pyrido [4,3-d] pyrimidin-5 (6H) - (1-methylpiperidin- On (Compound No. 53)

Pyrido [4,3-d] pyrimidin-5 (6H) - (1-methylpiperidin- (Compound No. 54)

Pyridin-4-yl) pyrimidine-5 ((4-fluoropyrimidin- 6H) -one (Compound No. 55)

56) A mixture of 8-bromo-4- (4- (4-fluorophenoxy) phenylamino) -2- (1- methylpiperidin- -5 (6H) -one (Compound No. 56)

57) A mixture of 8-chloro-4- (4- (cyclohexyloxy) phenylamino) -2- (1- methylpiperidin- 6H) -one (Compound No. 57)

Pyrido [4,3-d] pyrimidin-5 (6H) -quinoline-3- -One hydrochloride (Compound No. 58)

59) A mixture of 8-chloro-4- (4-cyclohexylphenylamino) -2- (1 -methylpiperidin-4-ylamino) pyrido [4,3- d] pyrimidin-5 (6H) Hydrochloride (Compound No. 59)

60) A mixture of 8-bromo-4- (4- (3-fluorophenoxy) phenylamino) -2- (1- methylpiperidin- -5 (6H) -one (Compound No. 60)

61) 8-Bromo-2- (methyl (1-methylpiperidin-4-yl) amino) -4- (4- phenoxyphenylamino) pyrido [ 6H) -one hydrochloride (Compound No. 61)

Pyrimidoyl) -5- (6H) -carbamic acid tert-butyl ester was obtained in a similar manner as in ) -One (Compound No. 62)

Pyrido [4,3-d] pyrimidin-5 (6-fluoropyridin-2-yl) (6H) -one (Compound No. 63)

Pyridin-4-yl) pyrimidine-5 ((4-methylpiperidin- 6H) -one (Compound No. 64)

Pyrido [4,3-d] pyrimidin-5 (6H) - (2-methylpiperazin-1- (Compound No. 65)

66) 2- (4-Aminopiperidin-1-yl) -8-chloro-4- (4- (trifluoromethoxy) phenylamino) pyrido [ ) -One (Compound No. 66)

67) 2- (4-Aminopiperidin-1-yl) -4- (4-tert- butylphenylamino) -8-chloropyrido [4,3- d] pyrimidin- (Compound No. 67).

Examples of more specific compounds for use in the present invention include the following, including pharmaceutically acceptable salts, hydrates, or solvates thereof:

1) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- phenoxyphenylamino) pyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 01)

2) Preparation of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (methylsulfonyl) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 03)

3) Preparation of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (1,3- difluoropropan- 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 07)

4) 2- (l-Methylpiperidin-4-ylamino) -8-bromo-4- (4- phenoxyphenylamino) pyrido [ One (Compound No. 12)

5) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (4- phenoxyphenylamino) pyrido [ Hydrochloride (Compound No. 16)

6) Preparation of 8- bromo-4- (4- (cyclopentyloxy) phenylamino) -2- (1 -methylpiperidin-4-ylamino) pyrido [ 6H) -one hydrochloride (Compound No. 21)

7) 8-Bromo-4- (4-isopropyl-3-methylphenylamino) -2- (1- methylpiperidin- 6H) -one hydrochloride (Compound No. 24)

8) Bromo-4- (4-tert-butylphenylamino) -2- (1 -methylpiperidin- -One hydrochloride (Compound No. 25)

Pyrimido-5 (6H) - (4-fluorophenyl) pyrimidin-4-yl] Hydrochloride (Compound No. 30)

Pyrimidin-5 (6H) -one (10 mg) was obtained in the same manner as in the synthesis of 8-bromo-2- (piperazin-1 -yl) -4- Hydrochloride (Compound No. 33)

Pyrimidoyl) pyrido [4,3-d] pyrimidin-4-yl) Pyrimidin-5 (6H) -one (Compound No. 36)

12) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (trifluoromethoxy) phenylamino) pyrido [ 6H) -one hydrochloride (Compound No. 41)

13) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (cyclopentyloxy) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 44)

Pyrimidin-5 < / RTI > (6H) - (4-methylpiperidin- (Compound No. 54)

Pyrido [4,3-d] pyrimidin-5 (6H) -quinoline-4-carboxylic acid ) -One (Compound No. 62)

16) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (4- (trifluoromethoxy) phenylamino) pyrido [ (6H) -one (Compound No. 63)

17) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- tert- butylphenylamino) pyrido [4,3- d] pyrimidin- (Compound No. 65)

18) 2- (4-Aminopiperidin-1-yl) -8-chloro-4- (4- (trifluoromethoxy) phenylamino) pyrido [ ) -One (Compound No. 66)

19) 2- (4-Aminopiperidin-1-yl) -4- (4-tert- butylphenylamino) -8-chloropyrido [4,3- d] pyrimidin- (Compound No. 67).

Examples of pharmaceutically acceptable salts of the compounds of formula (I) include the alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts, acid addition salts, hydrate salts and the like And is preferably non-toxic and water-soluble. Preferred salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate; And salts of organic acids such as acetic acid, tartrate, lactate, stannate, tannate, maleate, succinate, fumarate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, Citrate, gluconate, and organic acid salts such as fatty acid salts.

Also included within the scope of the present invention are the hydrates and solvates of the compounds of formula (I). Such hydrates and solvates may be prepared by a known method, preferably non-toxic and water-soluble, and are hydrates or solvates in which 1 to 5 of the molecules of water or an alcohol-based solvent (particularly, ethanol, etc.) desirable.

The compound represented by Formula 1 is prepared by the process of Reaction Scheme 1 below.

[Reaction Scheme 1]

Figure pat00009

Wherein R 1 , R 2 , and R 3 are as defined in Formula 1 above.

In the above Reaction Scheme 1, ethyl 4-chloro-6-methyl-2- (methylthio) pyrimidine-5-carboxylate represented by Chemical Formula 2 is dissolved in acetic acid, acetonitrile, tetrahydrofuran, Is reacted with 1-2 equivalents of an amine such as an arylamine, benzylamine, methylsulfonyl aniline, indenyl amine, or benzofuryl amine (H 2 NR 2 , R 2 is as defined in formula (1) 3 < / RTI > The compound of formula (3) may be reacted by heating with 1 to 3 equivalents of DMF-DMA in a dimethylformamide solvent to obtain the compound of formula (4). The compound of formula (5) can be prepared by cyclizing the compound of formula (4) using 2 to 4 equivalents of aqueous ammonia in an alcohol solvent. When the compound of formula (5) is subjected to a chlorination or bromination reaction using N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) in an organic solvent such as dichloromethane, chloroform or dimethylformamide, 6 can be prepared. Reacting the compound of formula 6 with mCPBA (1 to 3 equivalents) or hydrogen peroxide (1 to 3 equivalents) in an organic solvent such as dichloromethane, chloroform, N, N-dimethylformamide or dioxane to activate methylthio ), And then reacted with amines such as piperazine, aminopyrrolidine, aminopiperidine, etc. to prepare a compound of formula (1).

The synthetic process of Scheme 1 can be utilized with reference to known methods (Bioorganic & Medicinal Chemistry 15 (2007) 1044-1055, US 7,449,456 (Astellas Pharma), US 2005/0209221 (AMGEN), US 6,432,963 Yamanouchi Pharmaceutical Co., Ltd., US 2009/0054395 (PFIZER)).

The present invention also relates to a pharmaceutical composition comprising, as an active ingredient, a pyridopyrimidine derivative of formula (I), a pharmaceutically acceptable salt, hydrate or solvate thereof, as well as a prophylactic or therapeutic agent for osteoporosis A pharmaceutical composition is provided. As the above acceptable carriers, conventionally used excipients, disintegrants, sweeteners, lubricants or flavors can be used. The composition may be prepared in the form of tablets, capsules, powders, granules, suspensions, emulsions, syrups, injections or the like by a conventional method, or may be prepared in the form of unit dosage forms such as parenteral dosage forms May be formulated into pharmaceutical preparations.

The composition of the present invention may be administered parenterally or orally, and may be administered orally or parenterally on a daily basis in an amount of 0.5 to 5 mg / kg body weight, preferably 1 to 4 mg / kg body weight And in the case of oral administration in an amount of 5 to 50 mg / kg body weight, preferably 10 to 40 mg / kg body weight. The dosage for a patient may vary depending on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate, severity of disease, etc. of each patient.

Since the pyridopyrimidine derivative-containing pharmaceutical composition of the present invention promotes differentiation of osteoblast to increase bone mass and bone density, it can be used not only for prevention and treatment of metabolic bone diseases such as osteoporosis, but also for bone formation during growing period. In addition, the pharmaceutical composition of the present invention can be used as a therapeutic agent for various metabolic bone diseases such as nephrotic syndrome, osteomalacia, Paget's disease, osteogenesis imperfecta, and can also be used as a therapeutic agent for the treatment of fracture and bone cancer metastasis have.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example 1: Synthesis of 8-bromo-2- (4-methylpiperazin-1 -yl) -4- (4- (trifluoromethoxy) phenylamino) pyrido [4,3- (6H) -one (Compound No. 62)

Step 1 Preparation of ethyl 4-methyl-2- (methylthio) -6- (4- (trifluoromethoxy) phenylamino) pyrimidine-5-carboxylate

To a solution of ethyl 4-chloro-6-methyl-2- (methylthio) pyrimidine-5-carboxylate (1.85 g, 7.52 mmol) And then 4- (3-fluorophenoxy) aniline hydrochloride (1.65 g, 1.0 eq) was added thereto, followed by heating and refluxing for 3 hours. The resulting compound was concentrated under reduced pressure to remove the solvent. To the residue was added 30 ml of saturated sodium hydrogencarbonate solution to neutralize, followed by extraction with dichloromethane (50 ml x 2). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained material was recrystallized (ethyl acetate) to obtain 2.56 g (yield: 88%) of pure target compound as a white solid compound.

m / s [M + 1] = 388.0

1 H NMR (300 MHz, CDCl 3): 10.69 (s, NH), 7.96 (d, 2H), 7.22 (d, 2H), 4.40 (q, 2H), 2.67 (s, 3H), 2.52 (s, 3H), 1.48 (t, 3H)

Step 2 (E) - Preparation of ethyl 4- (2- (dimethylaminovinyl) -2- (methylthio) -6- (4- (trifluoromethoxy) phenylamino) pyrimidine-5-carboxylate

To a solution of ethyl 4-methyl-2- (methylthio) -6- (4- (trifluoromethoxy) phenylamino) pyrimidine-5-carboxylate (2.50 g, 6.45 mmol), N , And N-dimethylformamide dimethylacetal (1.15 g, 1.5 eq.) Were added. After stirring at room temperature, the temperature was gradually raised, and the mixture was stirred at 130 ° C for 16 hours. After the reaction was confirmed by TLC, the reaction solvent was removed by concentration under reduced pressure, and heptane (20 ml) was added to the concentrate. The reaction was stirred at room temperature for 3 hours and filtered to give 2.28 g (yield 80%) of the desired compound as a yellow solid.

m / s [M + 1] = 447.1

1 H NMR (300 MHz, CDCl 3): 8.15 (d, 2H), 7.92 (d, 2H), 6.03 (dd 1H), 4.40 (q, 2H), 3.30 (s, 6H), 2.56 (s, 3H ), 1.49 (t, 3H)

Step 3: Synthesis of 2- (methylthio) -4- (4- (trifluoromethoxy) phenylamino) pyrido [4,3- d] pyrimidin-5 (6H)

To a high pressure reactor were added ethanol (20 ml), (E) -ethyl 4- (2- (dimethylaminovinyl) -2- (methylthio) -6- (4- (trifluoromethoxy) phenylamino) pyrimidin- Carboxylate (2.20 g, 6.00 mmol) and 30% -NH 4 OH (3.5 ml, 5 eq.) Were added in this order and the mixture was stirred for 5 hours at 100 ° C. The reaction was slowly cooled to room temperature, Filtered, washed with ethanol and dried to give 1.77 g (yield 80%) of the desired compound as a yellow solid.

m / s [M + 1] = 369.1

1 H NMR (300 MHz, DMSO -d 6): 7.90 (d, 2H), 7.60 (d, 2H), 7.40 (d, 2H), 6.37 (d, 1H), 2.50 (s, 3H)

<Step 4> Synthesis of 8-bromo-2- (methylthio) -4- (4- (trifluoromethoxy) phenylamino) pyrido [4,3-d] pyrimidin-5 (6H)

To a solution of 2- (methylthio) -4- (4- (trifluoromethoxy) phenylamino) pyrido [4,3-d] pyrimidin-5 (6H) -one (1.00 g, 2.71 mmol) and N-bromosuccinimide (NBS, 0.63 g, 1.3 eq.) Were added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethanol was added to the concentrate, stirred at room temperature for 2 hours, filtered and dried to obtain 1.05 g (yield 87%) of the desired compound as a yellow solid.

m / s [M + 1] = 448.9

1 H NMR (300 MHz, DMSO -d 6): 8.00 (d, 1H), 7.88 (d, 2H), 7.42 (d, 2H), 2.56 (s, 3H)

Step 5 A mixture of 8-bromo-2- (4-methylpiperazin-1-yl) -4- (4- (trifluoromethoxy) phenylamino) pyrido [ (6H) -one (Compound No. 62)

To a solution of 8-bromo-2- (methylthio) -4- (4- (trifluoromethoxy) phenylamino) pyrido [4,3-d] pyrimidin-5 (6H) 0.90 g, 2.00 mmol), and the reaction solution was cooled to -20 캜. m-CPBA (1.48 g, 3 eq.) was added dropwise at -20 째 C, stirred for 30 minutes, then gradually warmed to room temperature, and triethylamine (0.83 mL, 3 equivalents) was added thereto and stirred at room temperature for 30 minutes. 1-Methylpiperidin-4-amine (342 mg, 1.5 eq.) Was added and the mixture was stirred at room temperature for 15 hours. Water (30 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The resulting solid was filtered, washed with alcohol (20 mL), and dried to obtain 0.54 g of a white target compound (yield: 54%).

m / s [M + 1] = 501.0

1 H NMR (300 MHz, DMSO -d 6): 7.91 (s, 1H), 7.88 (d, 2H), 7.38 (d, 2H), 3.97 (q, 4H), 3.34 (q, 4H), 2.50 ( s, 3H)

<Step 6> A solution of 8-bromo-2- (4-methylpiperazin-1 -yl) -4- (4- (trifluoromethoxy) phenylamino) pyrido [ (6H) -one methanesulfonate

To a solution of 8-bromo-2- (4-methylpiperazin-1-yl) -4- (4- (trifluoromethoxy) phenylamino) pyrido [4,3- d] pyrimidine- 5 (6H) -one (0.5 g, 1.00 mmol) was added thereto. After stirring at room temperature for 30 minutes, methanesulfonic acid (0.2 g, 2.1 eq.) Was added dropwise and the mixture was stirred at room temperature for 15 hours. The resulting reaction product was filtered, washed with ethyl acetate, and dried to obtain 0.60 g (yield: 86%) of a white target compound as a white solid.

m / s [M + 1] = 501.0

1 H NMR (300 MHz, DMSO -d 6): 7.91 (m, 1H), 7.88 (d, 2H), 7.38 (d, 2H), 3.97 (m, 4H), 3.34 (m, 4H), 2.50 ( s, 3H)

Example 2: 2- (4-Aminopiperidin-1-yl) -4- (4-tert-butylphenylamino) -8- chloropyrido [4,3- d] pyrimidin- -One (Compound No. 67)

<Step 1> Synthesis of ethyl 4- (4- (tert-butylphenylamino) -6-methyl-2- (methylthio) pyrimidine-5-carboxylate

To a solution of ethyl 4-chloro-6-methyl-2- (methylthio) pyrimidine-5-carboxylate (3.32 g, 13.46 mmol) And then 4- (tert-butyl) aniline (2.01 g, 1.0 eq.) Was added thereto, followed by heating and refluxing for 3 hours. The resulting compound was concentrated under reduced pressure to remove the solvent. The residue was neutralized with 50 ml of a saturated sodium hydrogen carbonate solution and extracted with dichloromethane (50 ml x 2). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained material was recrystallized (ethyl acetate) to obtain 4.57 g (yield: 94%) of pure objective compound as a white solid compound.

m / s [M + 1] = 361.15

1 H NMR (300 MHz, CDCl 3): 7.60 (d, 2H), 7.40 (d, 2H), 4.45 (q, 2H), 2.66 (s, 3H), 2.55 (s, 3H), 1.47 (t, 3H), &lt; / RTI &gt; 1.35 (s, 9H)

Step 2 To a solution of ethyl 4- (4- (tert-butylphenylamino) -6- (2- (dimethylamino) vinyl) -2- (methylthio) pyrimidine-

To a solution of ethyl 4- (4- (tert-butylphenylamino) -6-methyl-2- (methylthio) pyrimidine-5-carboxylate (4.58 g, 12.70 mmol), N, N Dimethylformamide dimethylacetal (2.27 g, 1.5 eq.), Stirred at room temperature, slowly heated and stirred for 16 hours at 130 DEG C. After confirming the reaction by TLC, the reaction solvent was removed by concentration under reduced pressure, and heptane ) Was added. The reaction was stirred at room temperature for 3 hours and filtered to give 4.21 g (yield 80%) of the title compound as a brown solid.

m / s [M + 1] = 416.2

1 H NMR (300 MHz, CDCl 3): 7.90 (d, 2H), 7.60 (d, 2H), 7.40 (d, 1H), 6.50 (d, 1H), 2.62 (s, 3H), 1.34 (s, 9H)

Step 3: Synthesis of 4- (4-tert-butylphenylamino) -2- (methylthio) pyrido [4,3-d] pyrimidin-5 (6H)

To a high pressure reactor were added ethanol (100 ml), ethyl 4- (4- (tert-butylphenylamino) -6- (2- (dimethylamino) vinyl) -2- (methylthio) pyrimidine- g, 10.16 mmol) and 30% -NH 4 OH (8.0 ml) were sequentially added and the mixture was stirred for 5 hours at 100 ° C. The reaction mixture was slowly cooled to room temperature, and the resulting solid was filtered, washed with ethanol, 1.50 g (yield 43%) of the aimed compound as a yellow solid was prepared.

m / s [M + 1] = 341.0

1 H NMR (300 MHz, DMSO -d 6): 7.75 (d, 2H), 7.43 (d, 2H), 7.41 (d, 1H), 6.45 (d, 1H), 2.62 (s, 3H), 1.36 ( t, 9H)

Step 4: Synthesis of 4- (4-tert-butylphenylamino) -8-chloro-2- (methylthio) pyrido [4,3- d] pyrimidin-5 (6H)

Pyrimido-5 (6H) -one (1.00 g, 2.94 mmol) in dimethylformamide (15 ml) , N-chlorosuccinimide (NCS, 0.51 g, 1.3 eq.), And the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethanol was added to the concentrate, stirred at room temperature for 2 hours, filtered and dried to obtain 0.52 g (yield: 48%) of yellow compound as a target compound.

m / s [M + 1] = 375.1

1 H NMR (300 MHz, DMSO -d 6): 8.00 (d, 1H), 7.88 (d, 2H), 7.42 (d, 2H), 2.62 (s, 3H), 1.36 (s, 9H)

Step 5: Preparation of 2- (4-aminopiperidin-1-yl) -4- (4-tert-butylphenylamino) -8- chloropyrido [4,3- d] pyrimidin- -One (Compound No. 67)

To a solution of 4- (4-tert-butylphenylamino) -8-chloro-2- (methylthio) pyrido [4,3- d] pyrimidin-5 (6H) -one (50 mg, 0.133 mmol ) And the reaction solution was cooled to -10 ° C. To this was added m-CPBA (90 mg, 3 eq.) Dropwise at -10 째 C, stirred for 30 minutes, slowly warmed to room temperature, and then triethylamine (0.33 mL, 3 equivalents) was added and stirred at room temperature for 30 minutes. To this was added piperidin-4-amine (20 mg, 1.5 eq.) And the mixture was stirred at room temperature for 15 hours. Water (30 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The resulting solid was filtered, washed with alcohol (20 mL) and dried to obtain 26 mg of a white target compound (yield: 45%).

m / s [M + 1] = 427.2

1 H NMR (300 MHz, DMSO -d 6): 7.91 (s, 1H), 7.88 (d, 2H), 7.38 (d, 2H), 4.20 (q, 2H), 3.35 (s, 3H), 3.01 ( (d, 2H), 7.42 (d, 2H), 3.30-1.80 (m, 9H), 1.36 (s, 3H), 1.29 , 9H)

Example 3: Preparation of 8-bromo-2- (1-methylpiperidin-4-ylamino) -4- (4-phenoxyphenylamino) pyrido [ ) -One hydrochloride (Compound No. 16)

Step 1 Ethyl 4-methyl-2- (methylthio) -6- (4-phenoxyphenylamino) pyrimidine-5-carboxylate

To a solution of ethyl 4-chloro-6-methyl-2- (methylthio) pyrimidine-5-carboxylate (5.00 g, 20.27 mmol) 4-phenoxyaniline (3.75 g, 1.0 eq) was added thereto, and the mixture was heated and refluxed for 3 hours. The resulting compound was concentrated under reduced pressure to remove the solvent. The residue was neutralized with 50 ml of a saturated sodium hydrogencarbonate solution and extracted with dichloromethane (75 ml x 2). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting material was recrystallized (MTBE) to obtain 7.77 g (yield: 97%) of pure target compound as a white solid compound.

1 HNMR (300MHz, CDCl 3) δ (ppm): 10.58 (s, 1H), 7.59-7.62 (m, 2H), 7.34-7.38 (m, 2H), 7.08-7.12 (m, 1H), 7.0-7.08 (m, 4H), 4.40-4.46 (m, 2H), 2.67 (s, 3H), 2.51 (s, 3H), 1.44-1.47 (q, J = 7.12 Hz, 3H).

<Step 2> (E) -Ethyl 4- (2- (dimethylamino) vinyl) -2- ( Methyl thio ) -6- (4- Phenoxyphenylamino ) Pyrimidin-5- Carboxylate

To a solution of ethyl 4-methyl-2- (methylthio) -6- (4-phenoxyphenylamino) pyrimidine-5-carboxylate (7.50 g, 18.96 mmol), N, Formamide dimethylacetal (3.39 g, 1.5 eq.) Were added. After stirring at room temperature, the temperature was gradually raised, and the mixture was stirred at 130 ° C for 5 hours. After the reaction was confirmed by TLC, the reaction solvent was removed by concentration under reduced pressure, and heptane (60 ml) was added to the concentrate. The reaction was stirred at room temperature for 3 hours and filtered to obtain 7.26 g (yield 85%) of the desired compound as a yellow solid

m / s [M + 1] = 451.1

1 H NMR (300M Hz, CDCl 3) δ (ppm): 10.61 (s, 0.4H), 10.53 (s, 0.6H), 8.12 (d, 1H), 7.61-7.65 (m, 2H), 7.32-7.37 (m, 2H), 7.09-7.12 (m, 1H), 6.99-7.02 (m, 4H), 6.08 (d, 0.4H), 5.97 (s, 3H), 2.50 (s, 3H), 1.45 (q, 1.2H).

Step 3: Synthesis of 2- (methylthio) -4- (4-phenoxyphenylamino) pyrido [4,3-d] pyrimidin-5 (6H)

To a high-pressure reactor were added ethanol (60 ml), (E) -ethyl 4- (2- (dimethylamino) vinyl) -2- (methylthio) -6- (4-phenoxy (6.60 g, 14.65 mmol) NH 4 OH (10.5 ml, 5 eq.) Were added in this order and stirred for 5 hours at 100 ° C. The reaction was slowly cooled to room temperature and the resulting solid was filtered, washed with ethanol and dried to obtain the desired compound 4.13 g (yield 75%).

m / s [M + 1] = 377.1

1 H NMR (300M Hz, DMSO -d 6) δ (ppm): 11.95 (s, 1H), 11.92 (bs, 1H), 7.76-7.79 (m, 2H), 7.56 (d, 1H), 7.37-7.42 (m, 2H), 7.12-7.15 (m, IH), 7.01-7.08 (m, 4H), 6.32

<Step 4> 8- Bromo -2-( Methyl thio ) -4- (4- ( Phenoxyphenylamino ) Pyrido [4,3-d] pyrimidin-5 (6H) -one

To a solution of 2- (methylthio) -4- (4-phenoxyphenylamino) pyrido [4,3-d] pyrimidin-5 (6H) -one (4.00 g, 10.63 mmol) in dimethylformamide (60 ml) N-Bromosuccinimide (NBS, 2.46 g, 1.3 eq.) Was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethanol was added to the concentrate, stirred at room temperature for 2 hours, filtered and dried to obtain 5.83 g (yield: 83%) of the desired compound as a yellow solid.

m / s [M + 1] = 455/457

1 H NMR (300M Hz, DMSO -d 6) δ (ppm): 12.30 (bs, 1H), 12.01 (s, 1H), 8.01 (s, 1H), 7.78-7.76 (m, 2H), 7.40 (m , 2H), 7.16 (m, 1H), 7.02-7.08 (m, 4H), 2.56 (s, 3H).

Step 5: Preparation of 8-bromo-2- (4-methylpiperidin-4-ylamino) -4- (4- phenoxyphenylamino) pyrido [4,3- d] pyrimidin- )-On

To a solution of 8-bromo-2- (methylthio) -4- (4- (phenoxyphenylamino) pyrido [4,3-d] pyrimidin-5 (6H) M-CPBA (4.44 g, 3 eq.) Was added dropwise thereto at -20 ° C, and the mixture was stirred for 30 minutes, then slowly warmed to room temperature, and triethylamine ( Amino-1-methylpiperidine (1.03 g, 1.5 eq.) Was added thereto, and the mixture was stirred at room temperature for 15 hours. To the reaction solution was added water 120 mL) was added thereto. The mixture was stirred at room temperature for 5 hours, filtered, washed with alcohol (50 mL) and dried to obtain 2.19 g (yield: 70.0%) of white solid.

m / s [M + 1] = 520/522

1 H NMR (300M Hz, DMSO -d 6) δ (ppm): 11.91 (s, 0.6H), 11.8 (s, 0.4H), 7.87 (d, 1H), 7.75-7.79 (m, 2H), 7.65 (d, 0.6H), 7.51 (d, 0.4H), 7.32-7.41 (m, 2H), 7.11-7.14 (m, 1H), 7.0-7.04 (m, 4H), 3.80-3.95 ), 3.6-3.75 (m, 0.6H), 2.7-2.90 (m, 2H), 2.13-2.17 (2s, 3H), 1.8-2.0 (m, 4H), 1.5-1.6 (m, 2H).

Step 6: To a solution of 8-bromo-2- (l-methylpiperidin-4-ylamino) -4- (4- phenoxyphenylamino) pyrido [ ) -One hydrochloride (Compound No. 16)

To a solution of 8-bromo-2- (1-methylpiperidin-4-ylamino) -4- (4-phenoxyphenylamino) pyrido [4,3- d] pyrimidin- 6H) -one (1.56 g, 3.00 mmol) was added thereto. The mixture was stirred at room temperature for 30 minutes, and then a 2.0 M hydrochloride ether solution (3.15 mL, 2.1 equivalents) was added dropwise thereto and stirred at room temperature for 15 hours. The resulting reaction product was filtered, washed with ethyl acetate, and dried to obtain 1.50 g (yield 90%) of a white target compound as a white solid.

m / s [M + 1] = 520/522

1 H NMR (300M Hz, DMSO -d 6) δ (ppm): 12.03 (s, 0.6H), 11.88 (s, 0.4H), 11.83 (d, 0.4H), 11.75 (d, 0.6H), 10.69 (m, 5H), 3.85-4.10 (m, 1H), 3.0 (m, 2H) -3.5 (m, 4H), 2.72 (s, 3H), 1.8-2.2 (m, 4H).

Test Example 1: Measurement of activity of alkaline phosphatase

In order to confirm the osteogenic differentiation promoting activity of the pyrido pyrimidine derivatives of the present invention synthesized in the above Examples and the like, the activity of the alkaline phosphatase, which is a marker of osteoblast differentiation, was examined in ST2 cells. ST2 cells with mesenchymal characteristics were cultured in RPMI1640 (Gibco) containing 10% fetal bovine serum (FBS, Gibco) at 37 ° C (5% CO 2 ). Cells were applied to 96-well plates at 4 x 10 3 per well. Cells were cultured for one day and treated with 0.0128, 0.064, 0.32, 1.6, 8, 40, 200 and 1000 nM of the compounds dissolved in DMSO. Regardless of the concentration of the compound, the DMSO concentration remained the same at 0.1%. After 72 hours of culture, the culture medium was removed, and 20 μL of 1% Triton X-100 was added to destroy the cells. After 12.5 μL of cell extract, 20 μL of 1 M p -nitrophenyl phosphate, and 0.1 N glycine-NaOH buffer (1: 1) were mixed and reacted at room temperature for 30 minutes, 100 μL of 0.1 N NaOH was added to stop the reaction . The absorbance at a wavelength of 405 nm was measured using an ELISA reader to evaluate the activity of the enzyme. A standard curve of absorbance and enzyme activity was obtained using a standard p - nitrophenol (Sigma) solution at a known concentration, and the absorbance results were converted into enzyme activities using this standard curve. The activity of increasing the activity of alkaline phosphatase was calculated by the increase ratio of the control cells treated with 0.1% DMSO alone to the alkaline phosphatase activity, and the EC 50 was calculated using GraphPad Prism 6 for Windows. The EC 50 of alkaline phosphatase-increasing activity is shown in Table 1 above.

Test Example 2: Measurement of bone mass and bone density in a magnetic white paper for osteoporosis treatment model

In order to confirm the bone formation promoting effect of the pyrido pyrimidine derivatives of the present invention synthesized in the above Examples and the like, the compounds were administered to osteoporosis induced osteoporosis-induced osteoporosis, and bone mineral density and bone mineral density were examined. An 11-week-old female SD (Sprague-Dawley) white paper (Harlan) was used for the experiment after being purified for 1 week. On the first day of the experiment, an ovariectomy was performed after anesthesia. At 8 weeks after the start of the experiment, the initial bone density was measured at a distance of 2 mm from the knee-side growth plate of the tibia using XCT Research SA equipment (StraTec Biomedical Systems). The compound was administered by forced oral administration method using Sonde daily from the ninth week starting from the beginning of the experiment for 8 weeks. At 4 weeks and 8 weeks after administration of the compound, bone mineral density of the same site was measured using XCT Research SA equipment. Bone mineral density and bone mineral density were calculated from the loop analysis (LOOP analysis) provided by the same equipment analysis program. The changes in the bone mass and bone density of the medullary bone were calculated in percent based on the bone mass and bone mineral density at the start of compound administration, and the mean ± standard errors are shown in Tables 2 and 3, respectively.

Changes in the bone mass of the cranial bone in the osteoporosis treatment model magnetic white paper 0 weeks 4 weeks 8 weeks Excipient 0.0 ± 0.0 11.3 ± 0.8 19.2 ± 1.1 Compound 16
10 mg / kg 0.0 ± 0.0 19.3 ± 0.9 28.1 ± 1.2 Alendronate
0.5 mg / kg 0.0 ± 0.0 13.5 ± 0.9 21.3 ± 1.2

Changes in BMD of bone-in-the-bone in osteoporosis model 0 weeks 4 weeks 8 weeks Excipient 0.0 ± 0.0 5.3 ± 0.2 8.4 ± 0.3 Compound 16
10 mg / kg 0.0 ± 0.0 7.0 ± 0.3 10.7 ± 0.3 Alendronate
0.5 mg / kg 0.0 ± 0.0 5.0 ± 0.3 8.6 ± 0.4

From the results shown in Tables 2 and 3, it can be seen that the use of the pyrido pyrimidine derivative of the present invention shows a better osteoporosis treatment effect in terms of bone mass and bone density than the case of using alendronate, which is a conventional therapeutic agent for osteoporosis.

Test Example 3: Estimation of bone mass and bone density in a model white osteoporosis prevention model

In order to confirm the bone formation promoting effect of the pyrido pyrimidine derivatives of the present invention synthesized in the above Examples and the like, the compounds were administered to osteoporosis induced osteoporosis-induced osteoporosis, and bone mineral density and bone mineral density were examined. An 11-week-old female SD (Sprague-Dawley) white paper (Harlan) was used for the experiment after being purified for 1 week. Initial bone density was measured at a distance of 2 mm from the knee-side growth plate of the tibia using an XCT Research SA instrument (StraTec Biomedical Systems). Osteoporosis was performed after the measurement of bone mineral density, and the compound was administered by forced oral administration method using Sonde every day for 8 weeks from 3 days. At 4 weeks and 8 weeks after administration of the compound, the bone mineral density at the same site was measured. Bone mineral density and bone mineral density were calculated from the loop analysis (LOOP analysis) provided by the same equipment analysis program. The change in bone mass and bone density of the medullary bone was calculated as a percentage based on the initial bone mass and bone density, and the mean ± standard error was shown in Tables 4 and 5, respectively.

Changes in the bone mass of the cranial bone in the osteoporosis-preventive model white paper 0 weeks 4 weeks 8 weeks Excipient 0.0 ± 0.0 10.6 ± 3.0 36.0 ± 5.5 Compound 62
10 mg / kg 0.0 ± 0.0 20.3 + 4.7 43.0 ± 6.0 Compound 16
3 mg / kg 0.0 ± 0.0 15.5 ± 3.8 39.3 ± 3.5 Compound 16
10 mg / kg 0.0 ± 0.0 14.5 ± 3.3 39.5 ± 5.2 Alendronate
0.5 mg / kg 0.0 ± 0.0 17.4 ± 2.3 41.4 ± 3.1

Changes in BMD of bone in bone in the osteoporosis prevention model 0 weeks 4 weeks 8 weeks Excipient 0.0 ± 0.0 4.5 ± 0.8 11.0 ± 0.8 Compound 62
10 mg / kg 0.0 ± 0.0 5.7 ± 0.8 12.1 ± 0.9 Compound 16
3 mg / kg 0.0 ± 0.0 5.1 ± 0.9 11.7 ± 0.7 Compound 16
10 mg / kg 0.0 ± 0.0 5.0 ± 0.4 13.3 ± 0.7 Alendronate
0.5 mg / kg 0.0 ± 0.0 3.6 ± 0.6 9.8 ± 0.6

From the results of Tables 4 and 5, it can be seen that the use of the pyrido pyrimidine derivative of the present invention shows a better osteoporosis prevention effect in terms of bone mass and bone density than the case of using alendronate, which is a conventional therapeutic agent for osteoporosis.

Claims (10)

A pharmaceutical composition for preventing or treating metabolic bone diseases, comprising a pyridopyrimidine derivative of the following formula 1, a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient:
[Chemical Formula 1]
Figure pat00010

In this formula,
R 1 is C 3-6 cycloalkylamino, piperazinyl, NC 1-3 alkylpiperazinyl, pyrrolidinyl, aminopyrrolidinyl, di C 1-3 alkylaminopyrrolidinyl, piperidinyl, aminopiper NC 1-3 alkylpiperidinyl, NC 1-3 alkylpiperidinylamino, or (NC 1-3 alkylpiperidinyl) (C 1-3 alkyl) amino;
R 2 is selected from the group consisting of halogen, C 1-4 alkyl optionally substituted with one or more halogens, C 1-4 alkoxy optionally substituted with one or more halogens, C 5-6 cycloalkyl, C 5-6 cycloalkyloxy , C 5-6 cycloalkyl methyloxy, C 6-12 aryl, C 6-12 aryloxy, C 6-12 aryl C 1-3 alkyloxy, methanesulfonyl, methoxycarbonyl, hydroxy carbonyl, C 6 -12 aryl-carbonyl and C 6-12 having at least one substituent selected from the group consisting of heteroaryl, 5-6 membered aryl (wherein the C 6-12 aryl, C 6-12 aryloxy and C 6-12 aryl C 1-3 alkyloxy may each independently be substituted with one or more halogens or methyl, and said heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O and S; Indenyl, unsubstituted or substituted with hydrogen; Benzofuryl substituted or unsubstituted with hydrogen; Or naphthalenyl which is unsubstituted or substituted by hydrogen;
R 3 is hydrogen, chlorine, bromine, or iodine. The method according to claim 1,
A pharmaceutical composition for preventing or treating metabolic bone disease, wherein R 1 is N-methylpiperazinyl, dimethylaminopyrrolidinyl, 4-aminopiperidinyl, or N-methylpiperidin-4-yl. The method according to claim 1,
Wherein said R 2 is 4-trifluoromethoxymonyl, 4-phenoxyphenyl, 4-cyclopentoxyphenyl, or 4-methanesulfonylphenyl. The method according to claim 1,
Wherein said R 3 is chlorine or bromine. The method according to claim 1,
Wherein said pharmaceutically acceptable salt is a hydrochloride, sulfate, acetate, formate, succinate, malate, fumarate, toluenesulfonate or methanesulfonate. The method according to claim 1,
Wherein the hydrate is one in which 1 to 5 water molecules are bound to the compound of Formula 1 and 1 to 5 alcohol molecules are bound to the compound of Formula 1 for preventing or treating metabolic bone disease &Lt; / RTI &gt; The method according to claim 1,
A pharmaceutical composition for preventing or treating metabolic bone disease, wherein the pyridopyrimidine derivative of formula (1), its pharmaceutically acceptable salt, hydrate or solvate is one of the following compounds:
1) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- phenoxyphenylamino) pyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 01)
2) Synthesis of (S) -methyl 4- (2- (3-aminopyrrolidin-1 -yl) -8-bromo-5-oxo-5,6-dihydropyrido [4,3- Methyl-benzoate hydrochloride (Compound No. 02)
3) Preparation of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (methylsulfonyl) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 03)
4) 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- isopropoxyphenylamino) pyrido [ Hydrochloride (Compound No. 04)
5) (R) -2- (3-Aminopyrrolidin-1-yl) -8-bromo-4- (4-isopropoxyphenylamino) pyrido [ 5 (6H) -one hydrochloride (Compound No. 05)
6) Synthesis of (S) -2- (3-aminopyrrolidin-1 -yl) -8-bromo-4- (4-isopropoxyphenylamino) pyrido [ 5 (6H) -one hydrochloride (Compound No. 06)
7) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (1, 3-difluoropropane-2-yloxy) phenylamino) pyrido [ 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 07)
8) (S) -2- (3-Aminopyrrolidin-1-yl) -8-bromo-4- (1,3- difluoropropan-2-yloxy) phenylamino) pyrido [ , 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 08)
9) Preparation of 2- (4-aminopiperidin-1-yl) -8-chloro-4- (4- (1, 3-difluoropropan-2-yloxy) phenylamino) pyrido [ 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 09)
10) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (2,3- dihydrobenzofuran- 5 -ylamino) pyrido [4,3- d] pyrimidine -5 (6H) -one hydrochloride (Compound No. 10)
11) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (5,6,7,8-tetrahydronaphthalen- ] Pyrimidin-5 (6H) -one hydrochloride (Compound No. 11)
Pyrido [4,3-d] pyrimidin-5 (6H) - (1-methylpiperidin- One (Compound No. 12)
13) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (oxazol- 6H) -one (Compound No. 13)
Pyrimidin-5 (6H) - (2-methylpiperidin-4-ylamino) pyrido [ (Compound No. 14)
Pyrimidin-2-ylmethyl) -pyrido [4,3-d] pyrimidin-4- Pyrimidin-5 (6H) -one (Compound No. 15)
16) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (4- phenoxyphenylamino) pyrido [ Hydrochloride (Compound No. 16)
17) 8-Bromo-4- (4- (cyclohexyloxy) phenylamino) -2- (1 -methylpiperidin- (6H) -one (Compound No. 17)
18) A mixture of 8-bromo-4- (4- (cyclohexylmethoxy) phenylamino) -2- (1 -methylpiperidin- (6H) -one (Compound No. 18)
19) 8-Chloro-4- (4- (cyclohexyloxy) phenylamino) -2- (1 -methylpiperidin- 6H) -one (Compound No. 19)
20) 8-Bromo-4- (4- (cyclopentylmethoxy) phenylamino) -2- (1 -methylpiperidin-4-ylamino) pyrido [4,3-d] pyrimidin- (6H) -one hydrochloride (Compound No. 20)
21) A mixture of 8-bromo-4- (4- (cyclopentyloxy) phenylamino) -2- (1 -methylpiperidin- 6H) -one hydrochloride (Compound No. 21)
D) pyrimidin-5 (6H) -one. &Lt; / RTI &gt; -One hydrochloride (Compound No. 22)
23) 8-Bromo-4- (2'-methyldiphenyl-4-ylamino) -2- (1- methylpiperidin- 5 (6H) -one hydrochloride (Compound No. 23)
24) 8-Bromo-4- (4-isopropyl-3-methylphenylamino) -2- (1- methylpiperidin- 6H) -one hydrochloride (Compound No. 24)
25) 8-Bromo-4- (4-tert-butylphenylamino) -2- (1- methylpiperidin- -One hydrochloride (Compound No. 25)
26) A mixture of 8-bromo-4- (4- (3,4-difluorophenoxy) phenylamino) -2- (1- methylpiperidin- ] Pyrimidin-5 (6H) -one hydrochloride (Compound No. 26)
Pyrido [4,3-d] pyrimidin-5 (6H) -quinolin-2- -One hydrochloride (Compound No. 27)
28) A mixture of 8-bromo-4- (4- (3,5-difluorophenoxy) phenylamino) -2- (1-methylpiperidin- ] Pyrimidin-5 (6H) -one (Compound No. 28)
29) 8-Bromo-4- (3-fluoro-4-phenoxyphenylamino) -2- (1 -methylpiperidin- 5 (6H) -one hydrochloride (Compound No. 29)
Pyrido [4,3-d] pyrimidin-5 (6H) - (4-fluorophenyl) Hydrochloride (Compound No. 30)
31) (R) -6- (3-Aminopyrrolidin-1-yl) -4-iodo-8- (4- (trifluoromethyl) phenylamino) isoquinolin- Hydrochloride (Compound No. 31)
32) (S) -6- (3-Aminopyrrolidin-1-yl) -4-bromo-8- (4- (trifluoromethyl) phenylamino) isoquinolin- Hydrochloride (Compound No. 32)
Pyrimidin-5 (6H) -one &lt; / RTI &gt; Hydrochloride (Compound No. 33)
34) (R) -2- (3-Dimethylamino) pyrrolidin-1-yl) -8-iodo-4- (4- phenoxyphenylamino) pyrido [ 5 (6H) -one (Compound No. 34)
Pyrido [4,3-d] pyrimidin-2-one (35 mg) was obtained as colorless crystals from 2- (4-aminopiperidin- Pyrimidin-5 (6H) -one hydrochloride (Compound No. 35)
Pyrido [4,3-d] pyrimidin-2-one (36 mg) as a colorless oil. Pyrimidin-5 (6H) -one (Compound No. 36)
37) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- methoxy- 3- methylphenylamino) pyrido [4,3- d] pyrimidin- ) -One hydrochloride (Compound No. 37)
38) Methyl 4- (2- (4-aminopiperidin-1 -yl) -8-bromo-5-oxo-5,6-dihydropyrido [4,3- d] pyrimidin- 6H) -one hydrochloride (Compound No. 38)
39) 2- (4-Aminopiperidin-l-yl) -8-bromo-4- (4- (4- fluorophenoxy) phenylamino) pyrido [ 5 (6H) -one hydrochloride (Compound No. 39)
40) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (3,4- difluorophenoxy) phenylamino) pyrido [ Pyrimidin-5 (6H) -one hydrochloride (Compound No. 40)
41) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (trifluoromethoxy) phenylamino) pyrido [ 6H) -one hydrochloride (Compound No. 41)
42) A mixture of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (3,4-fluorophenoxy) phenylamino) pyrido [ Methyl-5- (6H) -one hydrochloride (Compound No. 42)
43) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (3- isopropylphenylamino) pyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 43)
44) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (cyclopentyloxy) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 44)
45) Methyl 3- (2- (4-aminopiperidin-1-yl) -8-bromo-5-oxo-5,6-dihydropyrido [4,3- d] pyrimidin- 6H) -one hydrochloride (Compound No. 45)
4- (2,3-dihydrobenzofuran-5-ylamino) -2- (piperazin-1 -yl) pyrido [4,3-d] pyrimidin- ) -One hydrochloride (Compound No. 46)
Pyrimido-5 (6H) -quinolinone &lt; / RTI &gt; -One (Compound No. 47)
48) 2- (4-Aminopiperidin-1-yl) -4- (4-benzooxyl) phenylamino) -8-bromopyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 48)
49) 8-Bromo-4- (2,3-dihydro-1H-inden-5-ylamino) -2- (1 -methylpiperidin- ] Pyrimidin-5 (6H) -one (Compound No. 49)
2- (Piperazin-1 -yl) pyrido [4,3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 50)
51) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (2,3-dihydro- Yl) pyrido [4,3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 51)
52) A mixture of 8-chloro-4- (4- (cyclopentyloxy) phenylamino) -2- (1-methylpiperidin- ) -One (Compound No. 52)
Pyrido [4,3-d] pyrimidin-5 (6H) - (1-methylpiperidin- On (Compound No. 53)
Pyrido [4,3-d] pyrimidin-5 (6H) - (1-methylpiperidin- (Compound No. 54)
Pyridin-4-yl) pyrimidine-5 ((4-fluoropyrimidin- 6H) -one (Compound No. 55)
56) A mixture of 8-bromo-4- (4- (4-fluorophenoxy) phenylamino) -2- (1- methylpiperidin- -5 (6H) -one (Compound No. 56)
57) A mixture of 8-chloro-4- (4- (cyclohexyloxy) phenylamino) -2- (1- methylpiperidin- 6H) -one (Compound No. 57)
Pyrido [4,3-d] pyrimidin-5 (6H) -quinoline-3- -One hydrochloride (Compound No. 58)
59) A mixture of 8-chloro-4- (4-cyclohexylphenylamino) -2- (1 -methylpiperidin-4-ylamino) pyrido [4,3- d] pyrimidin-5 (6H) Hydrochloride (Compound No. 59)
60) A mixture of 8-bromo-4- (4- (3-fluorophenoxy) phenylamino) -2- (1- methylpiperidin- -5 (6H) -one (Compound No. 60)
61) 8-Bromo-2- (methyl (1-methylpiperidin-4-yl) amino) -4- (4- phenoxyphenylamino) pyrido [ 6H) -one hydrochloride (Compound No. 61)
Pyrimidoyl) -5- (6H) -carbamic acid tert-butyl ester was obtained in a similar manner as in ) -One (Compound No. 62)
Pyrido [4,3-d] pyrimidin-5 (6-fluoropyridin-2-yl) (6H) -one (Compound No. 63)
Pyridin-4-yl) pyrimidine-5 ((4-methylpiperidin- 6H) -one (Compound No. 64)
Pyrido [4,3-d] pyrimidin-5 (6H) - (2-methylpiperazin-1- (Compound No. 65)
66) 2- (4-Aminopiperidin-1-yl) -8-chloro-4- (4- (trifluoromethoxy) phenylamino) pyrido [ ) -One (Compound No. 66)
67) 2- (4-Aminopiperidin-1-yl) -4- (4-tert- butylphenylamino) -8-chloropyrido [4,3- d] pyrimidin- (Compound No. 67). 8. The method of claim 7,
A pharmaceutical composition for preventing or treating metabolic bone disease, wherein the pyridopyrimidine derivative of formula (1), its pharmaceutically acceptable salt, hydrate or solvate is one of the following compounds:
1) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- phenoxyphenylamino) pyrido [4,3- d] pyrimidin- Hydrochloride (Compound No. 01)
2) Preparation of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (methylsulfonyl) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 03)
3) Preparation of 2- (4-aminopiperidin-1-yl) -8-bromo-4- (4- (1,3- difluoropropan- 3-d] pyrimidin-5 (6H) -one hydrochloride (Compound No. 07)
4) 2- (l-Methylpiperidin-4-ylamino) -8-bromo-4- (4- phenoxyphenylamino) pyrido [ One (Compound No. 12)
5) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (4- phenoxyphenylamino) pyrido [ Hydrochloride (Compound No. 16)
6) Preparation of 8- bromo-4- (4- (cyclopentyloxy) phenylamino) -2- (1 -methylpiperidin-4-ylamino) pyrido [ 6H) -one hydrochloride (Compound No. 21)
7) 8-Bromo-4- (4-isopropyl-3-methylphenylamino) -2- (1- methylpiperidin- 6H) -one hydrochloride (Compound No. 24)
8) Bromo-4- (4-tert-butylphenylamino) -2- (1 -methylpiperidin- -One hydrochloride (Compound No. 25)
Pyrimido-5 (6H) - (4-fluorophenyl) pyrimidin-4-yl] Hydrochloride (Compound No. 30)
Pyrimidin-5 (6H) -one (10 mg) was obtained in the same manner as in the synthesis of 8-bromo-2- (piperazin-1 -yl) -4- Hydrochloride (Compound No. 33)
Pyrimidoyl) pyrido [4,3-d] pyrimidin-4-yl) Pyrimidin-5 (6H) -one (Compound No. 36)
12) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (trifluoromethoxy) phenylamino) pyrido [ 6H) -one hydrochloride (Compound No. 41)
13) 2- (4-Aminopiperidin-1-yl) -8-bromo-4- (4- (cyclopentyloxy) phenylamino) pyrido [ ) -One hydrochloride (Compound No. 44)
Pyrimidin-5 &lt; / RTI &gt; (6H) - (4-methylpiperidin- (Compound No. 54)
Pyrido [4,3-d] pyrimidin-5 (6H) -quinoline-4-carboxylic acid ) -One (Compound No. 62)
16) 8-Bromo-2- (l-methylpiperidin-4-ylamino) -4- (4- (trifluoromethoxy) phenylamino) pyrido [ (6H) -one (Compound No. 63)
17) 2- (4-Aminopiperidin-1 -yl) -8-bromo-4- (4- tert- butylphenylamino) pyrido [4,3- d] pyrimidin- (Compound No. 65)
18) 2- (4-Aminopiperidin-1-yl) -8-chloro-4- (4- (trifluoromethoxy) phenylamino) pyrido [ ) -One (Compound No. 66)
19) 2- (4-Aminopiperidin-1-yl) -4- (4-tert- butylphenylamino) -8-chloropyrido [4,3- d] pyrimidin- (Compound No. 67). The method according to claim 1,
Wherein the metabolic bone disease is osteoporosis. The method according to claim 1,
Wherein the pharmaceutical composition is in the form of tablets, capsules, powders, granules, suspensions, emulsions, syrups, or injections.
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WO2020159117A1 (en) * 2019-02-01 2020-08-06 주식회사 오스코텍 Oral solid formulation containing pyridopyridine-based hydrochloride and preparation method therefor
CN112566914A (en) * 2018-08-23 2021-03-26 奥斯考泰克公司 Crystalline polymorph of 8-bromo-2- (1-methylpiperidin-4-ylamino) -4- (4-phenoxyphenylamino) pyrido [4,3-d ] pyrimidin-5 (6H) -one hydrochloride and method for preparing same

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112566914A (en) * 2018-08-23 2021-03-26 奥斯考泰克公司 Crystalline polymorph of 8-bromo-2- (1-methylpiperidin-4-ylamino) -4- (4-phenoxyphenylamino) pyrido [4,3-d ] pyrimidin-5 (6H) -one hydrochloride and method for preparing same
JP2021535088A (en) * 2018-08-23 2021-12-16 オスコテック インコーポレイテッド Crystal polymorphs of 8-bromo-2- (1-methylpiperidin-4-ylamino) -4- (4-phenoxyphenylamino) pyrido [4,3-D] pyrimidine-5 (6H) -one hydrochloride and theirs Preparation method
JP2023071814A (en) * 2018-08-23 2023-05-23 オスコテック インコーポレイテッド Crystal polymorph of 8-bromo-2-(1-methylpiperidin-4-ylamino)-4-(4-phenoxyphenylamino)pyrido[4,3-d]pyrimidin-5(6h)-one hydrochloride, and method for preparing the same
US11731969B2 (en) 2018-08-23 2023-08-22 Oscotec Inc. Crystal polymorph of 8-bromo-2-(1-methylpiperidin-4-ylamino)-4-(4-phenoxyphenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one hydrochloride and method for preparing same
WO2020159117A1 (en) * 2019-02-01 2020-08-06 주식회사 오스코텍 Oral solid formulation containing pyridopyridine-based hydrochloride and preparation method therefor
KR20200095955A (en) * 2019-02-01 2020-08-11 주식회사 오스코텍 Oral solid formulation comprising pyridopyrimidin-based hydrochloride and preparation method thereof

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