KR20150042078A - Pharmaceutical composition comprising N-(2,2’-disubstituted-2H-cromene-6-yl)-N’,N”-disubstituted-guanidine derivatives for treating or preventing asthma or inflammation disease - Google Patents
Pharmaceutical composition comprising N-(2,2’-disubstituted-2H-cromene-6-yl)-N’,N”-disubstituted-guanidine derivatives for treating or preventing asthma or inflammation disease Download PDFInfo
- Publication number
- KR20150042078A KR20150042078A KR20130120831A KR20130120831A KR20150042078A KR 20150042078 A KR20150042078 A KR 20150042078A KR 20130120831 A KR20130120831 A KR 20130120831A KR 20130120831 A KR20130120831 A KR 20130120831A KR 20150042078 A KR20150042078 A KR 20150042078A
- Authority
- KR
- South Korea
- Prior art keywords
- dimethyl
- chromen
- nitrophenyl
- guanidine
- synthesis
- Prior art date
Links
- NOBGQKYDUMYXNA-UHFFFAOYSA-N CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc(cc1)ccc1[N+]([O-])=O)=N\N(CC1)CCN1c(cc1)ccc1F Chemical compound CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc(cc1)ccc1[N+]([O-])=O)=N\N(CC1)CCN1c(cc1)ccc1F NOBGQKYDUMYXNA-UHFFFAOYSA-N 0.000 description 1
- KQPRORXLQUAAFG-UHFFFAOYSA-N CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc(cc1)ccc1[N+]([O-])=O)=N\c(cccc1)c1OC Chemical compound CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc(cc1)ccc1[N+]([O-])=O)=N\c(cccc1)c1OC KQPRORXLQUAAFG-UHFFFAOYSA-N 0.000 description 1
- VQSHUZSVQNBSJL-UHFFFAOYSA-N CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc(cc1)ccc1[N+]([O-])=O)=N\c1ccccc1 Chemical compound CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc(cc1)ccc1[N+]([O-])=O)=N\c1ccccc1 VQSHUZSVQNBSJL-UHFFFAOYSA-N 0.000 description 1
- KXBKFWNKUBYKNX-UHFFFAOYSA-N CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc1ccccc1)=N\c(cc1)ccc1OC Chemical compound CC(C)(C=C1)Oc(cc2)c1cc2N/C(/Nc1ccccc1)=N\c(cc1)ccc1OC KXBKFWNKUBYKNX-UHFFFAOYSA-N 0.000 description 1
- HOLYSCKCKNDTHW-UHFFFAOYSA-N CC(C)(C=C1)Oc(cc2)c1cc2NC(Nc(cc1)ccc1[N+]([O-])=O)=S Chemical compound CC(C)(C=C1)Oc(cc2)c1cc2NC(Nc(cc1)ccc1[N+]([O-])=O)=S HOLYSCKCKNDTHW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 천식 또는 염증 질환의 예방 또는 치료에 유용하게 사용될 수 있는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition comprising a compound useful for prevention or treatment of asthma or inflammatory diseases or a pharmaceutically acceptable salt thereof.
에스-니트로소글루타치온 리덕타제(S-nitrosoglutathion reductase; GSNOR)은, 내생성 기관지 확장제인 에스-니트로소글루타치온(S-nitrosoglutathione; GSNO)의 대사를 조절하는 효소이며, Zinc와 NADH를 조효소로 사용한다.
S-nitrosoglutathion reductase (GSNOR) is an enzyme that regulates the metabolism of S-nitrosoglutathione (GSNO), an endogenous bronchodilator, and uses Zinc and NADH as coenzymes .
GSNO는 세포 내에서 글루타티온과 산화질소(nitric oxide)의 반응에 의해 생성되며, 안정적인 산화질소의 저장고 역할을 한다. 즉, 산화질소 자체는 활성을 나타낼 수 있는 반감기가 짧지만, GSNO는 산화질소의 저장고 역할을 함으로써 산화질소의 항상성을 유지할 수 있는 것으로 보고되고 있다. 실험 동물에 대해 천식 유발원으로서 자주 사용되는 난알부민(ovalbumin)을 항원으로 사용한 결과에 따르면 기도에서 GSNO 리덕타아제의 양이 증가하였으며, 그 결과 GSNO의 양은 감소하였다. 따라서, GSNO의 감소는 기도의 과민반응과 직접적으로 연관되는 것으로 증명되었다. 반면, GSNO 리덕타아제가 발현되지 않은 실험 동물에서는 GSNO의 양이 증가하였으며, 그 결과 난알부민 항원에 의해 야기될 수 있는 기도 과민반응이 발생하지 않았다. 이러한 실험 결과들은 GSNO 리덕타아제에 의해 대사되는 GSNO가 기도의 과민반응과 연관된다는 것을 나타내며, GSNO 리덕타아제의 활성을 억제하는 약물이 천식의 치료제로서 개발될 수 있다는 점을 시사한다.
GSNO is produced by the reaction of glutathione and nitric oxide in cells and serves as a reservoir of stable nitric oxide. That is, although the nitric oxide itself has a short half-life to exhibit its activity, it has been reported that GSNO can maintain homeostasis of nitrogen oxide by acting as a reservoir of nitric oxide. The amount of GSNO reductase in the airway increased as a result of the use of ovalbumin, which is frequently used as an asthmatic inducer in experimental animals, as an antigen. As a result, the amount of GSNO decreased. Thus, the reduction of GSNO has been shown to be directly related to the hypersensitivity of airway. On the other hand, the amount of GSNO was increased in experimental animals in which GSNO did not express lidocaine, and as a result, no airway hyperreactivity was caused by the albumin antigen. These results indicate that GSNO metabolized by GSNO reductase is associated with airway hyperresponsiveness, suggesting that a drug that inhibits the activity of GSNO reductase can be developed as a therapeutic agent for asthma.
실제로, N30 Pharmaceuticals사에서는 GSNO 리덕타아제의 억제제인 N6022 화합물을 임상시험하고 있다(Que, L.G. et al., 2005, Protection from experimental asthma by an endogenous bronchodilator, Science, 308, 1618-1621; Green, L.S. et al, 2012, Mechanism of inhibition for N6022, a first-in-class drug targeting S-nitrosoglutathione reductase, Biochemistry, 51(10), 2157-2168).
In fact, N30 Pharmaceuticals has been conducting clinical trials of the N6022 compound, an inhibitor of GSNO reductase (Que, LG et al., 2005, Protection from experimental asthma by an endogenous bronchodilator, Science, 308, 1618-1621; Mechanism of inhibition for N6022, a first-in-class drug targeting S-nitrosoglutathione reductase, Biochemistry, 51 (10), 2157-2168).
따라서, GSNOR의 활성을 효과적으로 저해할 수 있는 새로운 유기 저분자 약물성 선도물질 (lead compound)을 개발한다면, 기존 항염증 치료제의 단점을 극복하고 염증 효과를 억제함으로써 신규 항염증 치료제 개발이 가능해질 수 있을 것이다.
Therefore, if a new organic low-molecular-weight drug lead compound capable of effectively inhibiting the activity of GSNOR is developed, it may be possible to develop a novel anti-inflammatory drug by overcoming the disadvantages of existing anti-inflammatory drugs and suppressing the inflammatory effects will be.
한편, 본 발명자들은 벤조피란 골격을 가진 천연물 및 합성물이 광범위한 약리적 효능을 나타내는 사실에 착안하여 용액상 평형 합성기술을 이용하여 효율적으로 구아니딘계의 벤조피란 라이브러리를 구축할 수 있는 방법을 개발하고자 연구 노력하였다. 그 결과, 본 발명자가 기 발명한 한국등록특허 등록번호 제10-0547388호에 N-(2,2'-이중치환-2H-크로멘-6-일)-N',N"-이중치환-구아니딘 유도체를 개시한 바 있다.
On the other hand, the inventors of the present invention have focused on the fact that natural products and compounds having a benzopyran skeleton exhibit a wide range of pharmacological effects, and have developed a method for efficiently constructing a guanidine-based benzopyran library using a solution phase equilibrium synthesis technique Respectively. As a result, Korean Patent Registration No. 10-0547388, which was invented by the present inventors, discloses that N- (2,2'-disubstituted-2H-chromen-6-yl) -N ' Guanidine derivatives.
이에 본 발명자들은 상기 화합물의 다양한 용도를 검증하던 중, N-(2,2'-이중치환-2H-크로멘-6-일)-N',N"-이중치환-구아니딘 유도체가 상기 특허에 개시된 효능 이외에 GSNOR의 활성을 효과적으로 저해할 수 있음을 확인하여, 천식 또는 염증 질환의 예방 또는 치료에도 유용하게 사용될 수 있음을 확인하여 본 발명을 완성하였다.Accordingly, the inventors of the present invention have been studying various uses of the above-mentioned compounds and have found that N- (2,2'-disubstituted-2H-chromen-6-yl) -N ' The present inventors have confirmed that GSNOR activity can be effectively inhibited in addition to the disclosed effect and thus can be effectively used for prevention or treatment of asthma or inflammatory diseases.
본 발명은 천식 또는 염증 질환의 예방 또는 치료에 유용하게 사용될 수 있는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물을 제공하기 위한 것이다.The present invention provides a pharmaceutical composition comprising a compound useful for prevention or treatment of asthma or inflammatory diseases, or a pharmaceutically acceptable salt thereof.
상기 과제를 해결하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 천식 또는 염증 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating asthma or inflammatory diseases, which comprises, as an active ingredient, a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
상기 식에서, In this formula,
R1은 비치환되거나 또는 니트로로 치환된 페닐이고, R < 1 > is phenyl unsubstituted or substituted by nitro,
R2는 3,4-디옥소-벤질, 4-페닐-피페라진-1-일, 벤질 또는 페닐이고, 여기서 상기 R2는 비치환되거나 또는 C1 -4 알킬, C1 -4 알콕시, 할로겐 및 니트로로 구성되는 군으로부터 선택되는 1개 내지 3개의 치환기로 치환되고,R 2 is 3,4-dioxo-benzyl, 4-phenyl-piperazin-1-yl, benzyl or phenyl, wherein R 2 is unsubstituted or C 1 -4 alkyl, C 1 -4 alkoxy, halogen ≪ / RTI > and nitro, and < RTI ID = 0.0 >
R3는 수소 또는 C1 -4 알킬이고, 및R 3 is hydrogen or C 1 -4 alkyl, and
R4는 수소 또는 C1 -4 알킬이다.
R 4 is hydrogen or C 1 -4 alkyl.
본 발명에 따른 화합물은, 에스-니트로소글루타치온 리덕타제(S-nitrosoglutathion reductase; GSNOR)를 효과적으로 저해할 수 있으며, 이에 따라 GSNOR의 활성을 억제하여 이와 관련된 천식 또는 염증 질환의 예방 또는 치료에 사용될 수 있다. 본 발명의 일실시예에 따르면, 본 발명에 따른 화합물은 GSNOR을 효과적으로 저해할 수 있음을 확인하였으며, 이로부터 천식 또는 염증 질환의 예방 또는 치료에 사용될 수 있음을 확인하였다.
The compounds according to the present invention can effectively inhibit the S-nitrosoglutathion reductase (GSNOR) and thus inhibit the activity of GSNOR and can be used for the prevention or treatment of asthma or inflammatory diseases associated therewith have. According to one embodiment of the present invention, it has been confirmed that the compound according to the present invention can effectively inhibit GSNOR, and it can be used for the prevention or treatment of asthma or inflammatory diseases.
본 발명에서 사용되는 용어 "예방"은, 상기 약학적 조성물의 투여로 상기 질환을 억제 또는 지연시키는 모든 행위를 의미한다. 또한, 본 발명에서 사용되는 용어 "치료"는, 상기 약학적 조성물의 투여로 상기 질환의 증세가 호전되거나 완치되는 모든 행위를 의미한다.
The term "prophylactic " as used in the present invention means any action that inhibits or delays the disease by administration of the pharmaceutical composition. The term "treatment ", as used herein, refers to any action that improves or alleviates symptoms of the disease upon administration of the pharmaceutical composition.
본 발명에서의 약학적으로 허용 가능한 염은, 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 약제학적으로 허용 가능한 이들의 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약제학적으로 허용 가능한 염을 형성할 수도 있다.
The pharmaceutically acceptable salts in the present invention can be prepared by conventional methods in the art and include, for example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, Salts or pharmaceutically acceptable salts thereof with organic acids such as formic, acetic, oxalic, benzoic, citric, tartaric, gluconic, gestic, fumaric, lactobionic, salicylic, or acetylsalicylic acid (aspirin) Or react with an alkali metal ion such as sodium, potassium or the like to form a metal salt thereof, or react with an ammonium ion to form another form of a pharmaceutically acceptable salt.
또한, 본 발명에 따른 화합물들은 비대칭 탄소중심을 가질 수 있으므로 R 또는 S 이성체, 라세미체, 부분입체이성체 혼합물 및 개개 부분입체이성체로서 존재할 수 있으며, 이들 모든 이성체 및 혼합물은 본 발명의 범위에 포함된다.
In addition, the compounds according to the present invention may have asymmetric carbon centers and therefore may exist as R or S isomers, racemates, diastereomer mixtures and individual diastereomers, all of which areomers and mixtures are included within the scope of the present invention do.
상기 약학적 조성물은 추가적으로 약학적으로 허용되는 담체, 희석제 또는 부형제를 포함할 수 있다. 본 발명에서 사용되는 용어 '약학적으로 허용가능한 담체'는 유기체에 상당한 자극을 야기하지 않고, 투여되는 화합물의 생물학적 활성 및 성질을 폐기하지 않는 담체 또는 희석제를 의미한다. 또한, 본 발명에서 사용되는 용어 '약제학적으로 허용가능한 부형제'는 본 발명의 화학식 1의 화합물의 투여를 더욱 용이하게 하기 위해 약학적 조성물에 첨가되는 불활성 물질을 의미한다. 이러한 부형제의 예는 탄산 칼슘, 인산 칼슘, 다양한 유형의 당 및 전분, 셀룰로즈 유도체, 젤라틴, 식물성 오일 및 폴리에틸렌 글리콜이 있으며, 이에 한정되지 않는다.
The pharmaceutical composition may additionally comprise a pharmaceutically acceptable carrier, diluent or excipient. The term " pharmaceutically acceptable carrier " as used herein means a carrier or diluent that does not cause significant irritation to the organism and does not discard the biological activity and properties of the compound being administered. The term " pharmaceutically acceptable excipient " as used herein means an inert substance added to a pharmaceutical composition to further facilitate administration of the compound of formula (I) of the present invention. Examples of such excipients include, but are not limited to, calcium carbonate, calcium phosphate, various types of sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
또한, 본 발명의 약학적 조성물은 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구 투여용 제제로 제제화할 수 있다. 또한, 본 발명에 따른 화합물의 인체에 대한 투여 용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강 상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인환자를 기준으로 할 때 일반적으로 0.01 ㎎/일 내지 1000 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정 시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.
In addition, the pharmaceutical composition of the present invention can be prepared by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant, excipient and the like to the pharmaceutical preparations such as tablets, capsules, troches, A formulation for oral administration or a preparation for parenteral administration. The dose of the compound according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity. Generally, when administered to an adult patient having a body weight of 70 kg 0.01 mg / day to 1000 mg / day, and may be administered once or several times a day at a predetermined time interval according to the judgment of a doctor or pharmacist.
상기 화학식 1에서, 바람직하게는 상기 R1은 페닐, 또는 4-니트로페닐이다.
In the above formula (1), preferably, R 1 is phenyl or 4-nitrophenyl.
바람직하게는, 상기 R2는 3,4-디옥소-벤질; C1 -4 알콕시 또는 할로겐으로 치환된 4-페닐-피페라진-1-일; 할로겐으로 치환된 벤질; 또는 비치환되거나 또는 C1 -4 알킬, C1 -4 알콕시, 할로겐 및 니트로로 구성되는 군으로부터 선택되는 1개 내지 3개의 치환기로 치환된 페닐이다.
Preferably, the R 2 is 3,4-dioxo-benzyl; A C 1 -4 alkoxy or halogen substituted 4-phenyl-piperazin-1-yl; Benzyl substituted with halogen; Or unsubstituted or an unsubstituted or C 1 -4 alkyl, C 1 -4 alkoxy, substituted with one to three substituents selected from the group consisting of halo and nitrophenyl.
바람직하게는, 상기 R2는 3,4-디옥소-벤질, 4-(2-메톡시페닐)피페라진-1-일, 4-(3-메톡시페닐)피페라진-1-일, 4-(4-플루오로)피페라진-1-일, 4-(4-클로로)피페라진-1-일, 4-플루오로벤질, 페닐, 4-메틸페닐, 3,5-디메틸페닐, 2-메톡시페닐, 3-메톡시페닐, 4-메톡시페닐, 3,5-디메톡시페닐, 3,4,5-트리메톡시페닐, 4-플루오로페닐, 4-클로로페닐, 또는 4-니트로페닐이다.
Preferably, R 2 is selected from the group consisting of 3,4-dioxo-benzyl, 4- (2-methoxyphenyl) piperazin-1-yl, 4- (3- methoxyphenyl) piperazin- Yl, 4-fluorobenzyl, phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2-methylpiperazin-1-yl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, or 4-nitrophenyl to be.
바람직하게는, 상기 R3는 수소 또는 메틸이다.
Preferably, R < 3 > is hydrogen or methyl.
바람직하게는, 상기 R4는 수소 또는 에틸이다.
Preferably, R < 4 > is hydrogen or ethyl.
바람직하게는, 상기 R3는 수소이고 R4는 수소이거나, 또는 R3는 메틸이고 R4는 에틸이다.
Preferably, R 3 is hydrogen and R 4 is hydrogen, or R 3 is methyl and R 4 is ethyl.
상기 화학식 1로 표시되는 화합물의 바람직한 예는 다음과 같다.Preferable examples of the compound represented by the formula (1) are as follows.
1) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-니트로페닐)-3-페닐구아니딘,1) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-nitrophenyl)
2) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2,3-디페닐구아니딘,2) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2,3-diphenylguanidine,
3) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-플루오로페닐)-3-페닐구아니딘,3) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-fluorophenyl)
4) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(2-메톡시페닐)-3-페닐구아니딘,4) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (2-methoxyphenyl)
5) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-메톡시페닐)-3-페닐구아니딘,5) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-methoxyphenyl)
6) (Z)-2-(3,5-디메톡시페닐)-1-(2,2-디메틸-2H-크로멘-6-일)-3-페닐구아니딘,6) Synthesis of (Z) -2- (3,5-dimethoxyphenyl) -1- (2,2-dimethyl-2H-chromen-
7) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-페닐-2-(3,4,5-트리메톡시페닐)구아니딘,7) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -3-phenyl-2- (3,4,5-trimethoxyphenyl) guanidine,
8) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)-2-페닐구아니딘,8) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2- phenylguanidine,
9) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)-2-p-톨릴구아니딘,9) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2-
10) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(3,5-디메틸페닐)-3-(4-니트로페닐)구아니딘,10) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (3,5- dimethylphenyl) -3- (4-nitrophenyl) guanidine,
11) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-플루오로페닐)-3-(4-니트로페닐)구아니딘,11) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-fluorophenyl) -3-
12) (Z)-2-(4-클로로페닐)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,12) Synthesis of (Z) -2- (4-chlorophenyl) -1- (2,2-dimethyl-2H-chromen-
13) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(2-메톡시페닐)-3-(4-니트로페닐)구아니딘,13) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (2-methoxyphenyl) -3-
14) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-메톡시페닐)-3-(4-니트로페닐)구아니딘,14) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-methoxyphenyl) -3-
15) (Z)-2-(3,5-디메톡시페닐)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,15) Synthesis of (Z) -2- (3,5-dimethoxyphenyl) -1- (2,2-dimethyl-2H-chromen-
16) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)-2-(3,4,5-트리메톡시페닐)구아니딘,16) Synthesis of (Z) -l- (2,2-dimethyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2- (3,4,5-trimethoxyphenyl) guanidine,
17) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-플루오로벤질)-3-(4-니트로페닐)구아니딘,17) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2- (4- fluorobenzyl) -3- (4-nitrophenyl) guanidine,
18) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2,3-비스(4-니트로페닐)구아니딘,18) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2,3-bis (4-nitrophenyl) guanidine,
19) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-(2-메톡시페닐)피페라진-1-일)-3-(4-니트로페닐)구아니딘,1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4- (2- methoxyphenyl) piperazin- Nitrophenyl) guanidine,
20) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-(3-메톡시페닐)피페라진-1-일)-3-(4-니트로페닐)구아니딘,2- (4- (3-methoxyphenyl) piperazin-1 -yl) -3- (4- Nitrophenyl) guanidine,
21) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-(4-플루오로페닐)피페라진-1-일)-3-(4-니트로페닐)구아니딘,21) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2- (4- (4- fluorophenyl) piperazin- Nitrophenyl) guanidine,
22) (Z)-2-(4-(4-클로로페닐)피페라진-1-일)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,22) (Z) -2- (4- (4-Chlorophenyl) piperazin-1-yl) Phenyl) guanidine,
23) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-((3,4-디옥소사이클로헥사-1,5-디에닐)메틸)-3-(4-니트로페닐)구아니딘,Dimethyl-2H-chromen-6-yl) -2 - ((3,4-dioxocyclohexa-1,5-dienyl) methyl) -3- (4-nitrophenyl) guanidine,
24) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)-2-페닐구아니딘,24) (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-
25) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)-2-p-톨릴구아니딘,25) Synthesis of (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2-
26) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2-(2-메톡시페닐)-3-(4-니트로페닐)구아니딘,26) Synthesis of (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2- (2-methoxyphenyl) -3-
27) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2-(4-메톡시페닐)-3-(4-니트로페닐)구아니딘,27) Synthesis of (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2- (4-methoxyphenyl) -3-
28) (Z)-2-(3,5-디메톡시페닐)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,28) Synthesis of (Z) -2- (3,5-dimethoxyphenyl) -1- (2,7-dimethyl- ,
29) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)-2-(3,4,5-트리메톡시페닐)구아니딘,29) (Z) -1- (2,7-Dimethyl-2-propyl-2H-chromen- Phenyl) guanidine,
30) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2-(4-플루오로페닐)-3-(4-니트로페닐)구아니딘, 및30) (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2- (4-fluorophenyl) -3-
31) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2,3-비스(4-니트로페닐)구아니딘.
31) (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2,3-bis (4-nitrophenyl) guanidine.
또한, 본 발명은 하기 반응식 1과 같이, 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다. Further, the present invention provides a process for producing the compound represented by the above-mentioned formula (1) as shown in the following reaction formula (1).
[반응식 1][Reaction Scheme 1]
상기 반응식 1에서 R1, R2, R3, 및 R4는 각각 상기에서 정의한 바와 같고, ⓟ는 폴리스티렌-디비닐벤젠, 메타아크릴산-디메틸아크릴아미드 및 히드록실 메타아크릴산 중에서 선택된 고분자 중합체 형태의 고체 지지체를 나타낸다.
Wherein R 1 , R 2 , R 3 and R 4 are each as defined above, and wherein R 1 is a solid polymer in the form of a polymer selected from polystyrene-divinylbenzene, methacrylic acid-dimethyl acrylamide and hydroxyl methacrylic acid Lt; / RTI >
본 발명에 따른 제조과정 중에 합성되는 반응 중간체로서 상기 화학식 4로 표시되는 N-(2,2'-이중치환-2H-크로멘-6-일)-N'-싸이오우레아와, 본 발명이 목적하는 상기 화학식 1로 표시되는 N-(2,2'-이중치환-2H-크로멘-6-일)-N'-N"-이중치환-구아니딘 유도체 중에는 광학이성체가 존재하는바, 필요에 따라 공지된 분리 정제방법을 수행하여 각각의 순수한 광학이성체 화합물을 분리할 수도 있다.
(2, 2'-disubstituted-2H-chromen-6-yl) -N'-thiourea represented by Formula 4 as a reaction intermediate synthesized during the production process according to the present invention, The optical isomer is present in the desired N- (2,2'-disubstituted-2H-chromen-6-yl) -N'-N '' - disubstituted-guanidine derivative represented by the above formula Separation purification methods known in the art can also be performed to separate each pure optical isomer compound.
구체적으로, 상기 반응식 1에 따른 본 발명의 제조방법은, Specifically, the production method of the present invention according to Reaction Scheme 1,
1) 상기 화학식 2로 표시되는 화합물과 상기 화학식 3으로 표시되는 화합물을 반응시켜, 상기 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및1) reacting the compound represented by Formula 2 and the compound represented by Formula 3 to prepare a compound represented by Formula 4 (Step 1); And
2) 1,3-디이소프로필카보디이미드(DIC)와 디이소프로필에틸아민(DIPEA)의 존재 하에 상기 화학식 4로 표시되는 화합물과 상기 화학식 5로 표시되는 화합물을 반응을 시킨 후, 상기 반응 혼합물에 상기 화학식 6으로 표시되는 술포닐클로라이드기를 함유한 스케빈져 레진을 넣고 여과 및 농축하여, 상기 화학식 1로 표시되는 화합물을 제조하는 단계(단계 2)를 포함한다.
2) reacting the compound represented by the formula (4) with the compound represented by the formula (5) in the presence of 1,3-diisopropylcarbodiimide (DIC) and diisopropylethylamine (DIPEA) Adding a scavenger resin containing a sulfonyl chloride group represented by the formula (6) to the mixture, filtering and concentrating the mixture to prepare a compound represented by the formula (1) (step 2).
본 발명자들의 실험결과에 따르면, 상기 반응식 1로 표시되는 반응에서 단계 2에서 고체상 술포닐클로라이드 레진을 사용함으로써 동시에 많은 구아니딘계 벤조피란 유도체를 단기간에 합성할 수 있었다.
According to the experimental results of the present inventors, it was possible to synthesize many guanidine-based benzopyran derivatives in a short period of time simultaneously by using the solid-state sulfonyl chloride resin in the step 2 in the reaction represented by the above reaction scheme 1.
본 발명에 따른 반응공정, 용매계의 조성 및 반응조건의 선택범위를 구체적으로 설명하면 다음과 같다.
The selection range of the reaction process, the composition of the solvent system and the reaction conditions according to the present invention will be described in detail as follows.
본 발명에서 용매로서는 최종단계에 고체상 스케빈져 레진을 사용할 것을 고려하여 고체상 레진의 팽윤효과(Swelling effect)가 뛰어난 유기용매를 사용한다. 상기 단계 1에서는, 디클로로메탄(CH2Cl2), 클로로포름(CHCl3) 또는 테트라하이드로퓨란(THF)을 용매로 사용한다. 상기 반응에서, 상기 화학식 3으로 표시되는 화합물을 1.2 내지 2.0 당량 사용하는 것이 바람직하며, 보다 바람직하게는, 1.2 당량 사용할 수 있다.
As the solvent in the present invention, an organic solvent excellent in the swelling effect of the solid phase resin is used in consideration of the use of the solid phase scavenger resin in the final stage. In step 1, dichloromethane (CH 2 Cl 2 ), chloroform (CHCl 3 ), or tetrahydrofuran (THF) is used as a solvent. In the above reaction, 1.2 to 2.0 equivalents of the compound represented by the formula (3) is preferably used, and 1.2 equivalents may be more preferably used.
상기 단계 2에서는, 1,3-디이소프로필카보디이미드(DIC)와 디이소프로필에틸아민(DIPEA)을 1.0 내지 1.5 당량(바람직하기로는 1.2 당량) 존재 하에서 상기 화학식 5로 표시되는 화합물을 2.0 당량 이상의 과량 넣고 반응시키는 것이 바람직하다. 그 이유는 과량의 아민을 넣으면 목적하는 상기 화학식 1로 표시되는 화합물의 수율을 높일 수 있기 때문이다. 또한, 반응종료 후 미반응의 아민은 고체상 술포닐클로라이드 스케빈져 레진을 투입하여 여과함으로써 용이하게 제거할 수 있기 때문에 동시에 여러 개의 반응 및 반응 후 처리가 가능하다.
In the step 2, the compound represented by the formula (5) is reacted with 1.0 to 1.5 equivalents (preferably 1.2 equivalents) of 1,3-diisopropylcarbodiimide (DIC) and diisopropylethylamine It is preferable to carry out the reaction in an excess amount. This is because the excess amount of the amine can increase the yield of the target compound represented by the formula (1). After completion of the reaction, the unreacted amine can be easily removed by filtration of the solid phase sulfonyl chloride scavenger resin, so that it is possible to carry out a plurality of reactions and reactions after the reaction at the same time.
또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 생성 여부를 확인하기 위하여 반응 후 최종 단계에서 다중 컬럼크로마토그래피 장비(Quad3 +; 미국 Biotage사 제품) 및 자동 샘플주입장치가 있는 고속 액체크로마토그래피로 분리 정제한 다음 NMR 및 Mass 스펙트럼으로 구조를 분석 및 확인할 수 있으며, 본 발명의 실시예에서는 이를 통하여 구조를 분석 및 확인하였다. In addition, the multi-column at the final stage after reaction in order to determine whether to generate the formula (1) according to the present invention, the compounds chromatography equipment (Quad 3 +; US Biotage, Inc.) and high performance liquid chromatography with automated sample injection devices And then analyzed and confirmed by NMR and Mass spectroscopy. In the examples of the present invention, the structure was analyzed and confirmed.
본 발명에 따른 화합물은, 에스-니트로소글루타치온 리덕타제(S-nitrosoglutathion reductase; GSNOR)를 효과적으로 저해할 수 있으며, 이에 따라 GSNOR의 활성을 억제하여 이와 관련된 천식 또는 염증 질환의 예방 또는 치료에 유용하게 사용될 수 있다.The compounds according to the present invention can effectively inhibit the S-nitrosoglutathion reductase (GSNOR), thus inhibiting the activity of GSNOR and thus being useful for the prevention or treatment of asthma or inflammatory diseases associated therewith Can be used.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시에에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
제조예Manufacturing example : 중간체의 제조: Preparation of Intermediates
본 발명에 따른 화합물의 제조에 사용되는 중간체를 아래와 같이 제조하였다.
The intermediates used in the preparation of the compounds according to the invention were prepared as follows.
제조예Manufacturing example 1: 1-(2,2-디메틸-2H- 1: 1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-3--6-yl) -3- 페닐Phenyl -- 싸이오우레아의Thaiorea 제조 Produce
2,2-디메틸-2H-크로멘-6-아민(1.00 g, 5.7 mmol)을 디클로로메탄(DCM, 15 mL)에 녹인 후 상온에서 10분 동안 교반시킨 후, 페닐이소싸이오시안산 염(C6H4NCS; 0.92 g, 6.8 mmol, 1.2 eq)을 가하고, 같은 온도에서 15시간 동안 교반시켰다. 반응종료 후, 반응물을 감압 농축시키고 잔류물을 헥산/에틸아세테이트(4/1, v/v)의 혼합 용매 하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 표제화합물(1.15 g, 수율 65 %)을 얻었다. (1.00 g, 5.7 mmol) was dissolved in dichloromethane (DCM, 15 mL), and the mixture was stirred at room temperature for 10 minutes. Then, phenyl isothiocyanate (C 6 H 4 NCS; 0.92 g, 6.8 mmol, 1.2 eq) was added and stirred at the same temperature for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel in a mixed solvent of hexane / ethyl acetate (4/1, v / v) to give the title compound (1.15 g, yield 65% .
1H NMR(300 MHz, CDCl3) δ 8.23(d, 1H, J=7.9 Hz), 7.77(s, 1H), 7.39(s, 1H), 7.38-7.27(m, 2H), 7.14-7.08(m, 3H), 7.00(d, 2H), 6.82(d, 1H, J=8.5 Hz), 6.30(d, 1H, J=9.9 Hz), 5.69(d, 1H, J=9.9 Hz), 1.45(s, 6H); M/S 310.42
1 H NMR (300 MHz, CDCl 3) δ 8.23 (d, 1H, J = 7.9 Hz), 7.77 (s, 1H), 7.39 (s, 1H), 7.38-7.27 (m, 2H), 7.14-7.08 ( (d, 1H, J = 9.9Hz), 1.45 (d, 2H, J = s, 6H); M / S 310.42
제조예Manufacturing example 2: 1-(2,2-디메틸-2H- 2: 1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-3-(4-니트로--6-yl) -3- (4-nitro- 페닐Phenyl )-) - 싸이오우레아Thiourea 의 제조Manufacturing
2,2-디메틸-2H-크로멘-6-아민(1.00 g, 5.7 mmol)을 디클로로메탄(DCM, 15 mL)에 녹인 후 상온에서 10분간 교반시킨 후, 4-니트로페닐이소싸이오시안산 염(4-O2NC6H4NCS; 1.22 g, 6.8 mmol, 1.2 eq)을 가하고 같은 온도에서 15시간 동안 교반시켰다. 반응종료 후, 반응물을 감압 농축시키고 잔류물을 헥산/에틸아세테이트(4/1, v/v)의 혼합 용매 하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 표제 화합물을 노란색 고체(1.50 g, 수율 74 %)로 얻었다. 6-amine (1.00 g, 5.7 mmol) was dissolved in dichloromethane (DCM, 15 mL) and stirred at room temperature for 10 minutes. 4-Nitrophenylisothiocyanate (4-O 2 NC 6 H 4 NCS; 1.22 g, 6.8 mmol, 1.2 eq) and the mixture was stirred at the same temperature for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel in a mixed solvent of hexane / ethyl acetate (4/1, v / v) to give the title compound as a yellow solid (1.50 g, yield 74% ).
1H NMR(200 MHz, CDCl3) δ 8.20(d, 2H, J=9.2 Hz), 7.75(d, 2H, J=9.2 Hz), 7.07(m, 1H), 6.94-6.6.83(m, 2H), 6.30(d, 1H, J=9.8 Hz), 5.72(d, 1H, J=9.8 Hz), 1.47(s, 6H); M/S 355.44
1 H NMR (200 MHz, CDCl 3) δ 8.20 (d, 2H, J = 9.2 Hz), 7.75 (d, 2H, J = 9.2 Hz), 7.07 (m, 1H), 6.94-6.6.83 (m, 2H), 6.30 (d, 1H, J = 9.8 Hz), 5.72 (d, 1H, J = 9.8 Hz), 1.47 (s, 6H); M / S 355.44
제조예Manufacturing example 3: 1-(2,7-디메틸-2-프로필-2H- 3: 1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-3-(4-니트로--6-yl) -3- (4-nitro- 페닐Phenyl )-) - 싸이오우레아의Thaiorea 제조 Produce
상기 제조예 2와 동일한 방법으로 수행하되, 2,2-디메틸-2H-크로멘-6-아민 대신 2-메틸-2-프로필-2H-크로멘-6-아민을 사용하여, 표제 화합물을 얻었다. Methyl-2-propyl-2H-chromen-6-amine in place of 2,2-dimethyl-2H-chromen-6-amine, the title compound was obtained .
M/S 397.49
M / S 397.49
실시예Example 1: (Z)-1-(2,2-디메틸-2H- 1: (Z) -1- (2,2-dimethyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 니트로페닐Nitrophenyl )-3-) -3- 페닐구아니딘의Phenylguanidine 제조 Produce
제조예 1에서 제조한 1-(2,2-디메틸-2H-크로멘-6-일)-3-페닐-싸이오우레아(50 mg, 0.16 mmol, 1 eq)를 클로로포름(CHCl3, 5 mL)에 가한 후 상온에서 10분 동안 교반하였다. 1,3-디이소프로필카보디이미드(DIC; 0.029 mL, 0.19 mmol, 1.2 eq)와 디이소프로필에틸아민(DIPEA; 0.033 mL, 0.19 mmol, 1.2 eq)을 가하고 50℃에서 10분 동안 교반한 후 상기 반응물에 4-니트로아닐린(44 mg, 0.32 mmol)을 가하고 15시간 동안 교반하였다. 반응 종료 후, 상온으로 온도를 내리고 반응물에 폴리스타이렌 설포닐클로라이드(2.90 mmol/g, 0.35 g, 1 mmol)를 가한 후 30분 동안 교반시켰다. 반응 혼합물을 여과하고 여과물을 클로로포름(CHCl3)으로 반복 세척하고 여과액을 합하여 감압 농축한 다음 헥산/에틸아세테이트(3/1, v/v)의 혼합 용매 하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 표제화합물(35 mg, 수율 53 %)을 얻었다. 3-phenyl-thiourea (50 mg, 0.16 mmol, 1 eq) prepared in Preparation Example 1 was dissolved in chloroform (CHCl 3 , 5 mL ), And the mixture was stirred at room temperature for 10 minutes. Diisopropylcarbodiimide (DIC; 0.029 mL, 0.19 mmol, 1.2 eq) and diisopropylethylamine (DIPEA; 0.033 mL, 0.19 mmol, 1.2 eq) were added and stirred at 50 ° C for 10 min Then, 4-nitroaniline (44 mg, 0.32 mmol) was added to the reaction solution, and the mixture was stirred for 15 hours. After completion of the reaction, the temperature was lowered to room temperature, polystyrene sulfonyl chloride (2.90 mmol / g, 0.35 g, 1 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was filtered, and the filtrate was repeatedly washed with chloroform (CHCl 3 ). The filtrate was combined, concentrated under reduced pressure, and then purified by column chromatography on silica gel in a mixed solvent of hexane / ethyl acetate (3/1, v / v) To obtain the title compound (35 mg, yield 53%).
1H NMR(300 MHz, CDCl3) δ 8.08(d, 2H, J=8.9 Hz), 7.34-7.16(m, 7H), 6.90(dd, 1H, J=8.6 Hz, J=2.5 Hz), 6.82(d, 1H, J=2.5 Hz), 6.71(d, 1H, J=8.6 Hz), 6.23(d, 1H, J=9.8 Hz), 5.65(d, 1H, J=9.8 Hz), 1.41(s, 6H); M/S 414.46
1 H NMR (300 MHz, CDCl 3) δ 8.08 (d, 2H, J = 8.9 Hz), 7.34-7.16 (m, 7H), 6.90 (dd, 1H, J = 8.6 Hz, J = 2.5 Hz), 6.82 (d, IH, J = 9.8 Hz), 6.71 (d, IH, J = 9.8 Hz), 6.23 , 6H); M / S 414.46
이하 실시예 2 내지 31은, 상기 실시예 1과 동일한 방법으로 제조하되 각 목적 화합물의 화학구조에 맞는 출발물질을 사용하여 제조하였다.
Examples 2 to 31 were prepared in the same manner as in Example 1, except that the starting materials corresponding to the chemical structures of the target compounds were used.
실시예Example 2: (Z)-1-(2,2-디메틸-2H- 2: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2,3--6-yl) -2,3- 디페닐구아니딘의Diphenylguanidine 제조 Produce
M/S 369.45
M / S 369.45
실시예Example 3: (Z)-1-(2,2-디메틸-2H- 3: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 플루오로페닐Fluorophenyl )-3-) -3- 페닐구아니딘의Phenylguanidine 제조 Produce
1H NMR(300 MHz, CDCl3) δ 7.36-7.31(m, 5H), 7.01(m, 2H), 6.86(t, 2H, J=8.7 Hz), 6.65(d, 1H), 6.64-6.61(m, 2H), 6.32(d, 1H), 5.72(d, 1H), 1.43(s, 6H); M/S 387.46
1 H NMR (300 MHz, CDCl 3) δ 7.36-7.31 (m, 5H), 7.01 (m, 2H), 6.86 (t, 2H, J = 8.7 Hz), 6.65 (d, 1H), 6.64-6.61 ( m, 2 H), 6.32 (d, 1 H), 5.72 (d, 1 H), 1.43 (s, 6 H); M / S 387.46
실시예Example 4: (Z)-1-(2,2-디메틸-2H- 4: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(2--6-yl) -2- (2- 메톡시페닐Methoxyphenyl )-3-) -3- 페닐구아니딘의Phenylguanidine 제조 Produce
M/S 399.47
M / S 399.47
실시예Example 5: (Z)-1-(2,2-디메틸-2H- 5: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 메톡시페닐Methoxyphenyl )-3-) -3- 페닐구아니딘의Phenylguanidine 제조 Produce
1H NMR(300 MHz, CDCl3) δ 7.29-7.11(m, 7H), 6.95(d, 2H, J=8.1 Hz), 6.86-6.81(m, 2H), 6.67(d, 2H, J=7.2 Hz), 6.25(d, 1H), 5.62(d, 1H, J=9.9 Hz), 3.75(s, 3H), 1.38(s, 6H); M/S 399.47
1 H NMR (300 MHz, CDCl 3) δ 7.29-7.11 (m, 7H), 6.95 (d, 2H, J = 8.1 Hz), 6.86-6.81 (m, 2H), 6.67 (d, 2H, J = 7.2 Hz), 6.25 (d, 1H), 5.62 (d, 1H, J = 9.9Hz), 3.75 (s, 3H), 1.38 (s, 6H); M / S 399.47
실시예Example 6: (Z)-2-(3,5- 6: (Z) -2- (3,5- 디메톡시페닐Dimethoxyphenyl )-1-(2,2-디메틸-2H-) -1- (2,2-dimethyl-2H- 크로멘Kromen -6-일)-3--6-yl) -3- 페닐구아니딘의Phenylguanidine 제조 Produce
M/S 429.45
M / S 429.45
실시예Example 7: (Z)-1-(2,2-디메틸-2H- 7: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-3--6-yl) -3- 페닐Phenyl -2-(3,4,5--2- (3,4,5- 트리메톡시페닐Trimethoxyphenyl )구아니딘의 제조) Preparation of guanidine
M/S 459.46
M / S 459.46
실시예Example 8: (Z)-1-(2,2-디메틸-2H- 8: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )-2-)-2- 페닐구아니딘의Phenylguanidine 제조 Produce
1H NMR(300 MHz, CDCl3) δ 8.08(d, 2H, J=8.9 Hz), 7.34-7.16(m, 7H), 6.90(dd, 1H, J=8.6 Hz, J=2.5 Hz), 6.82(d, 1H, J=2.5 Hz), 6.71(d, 1H, J=8.6 Hz), 6.23(d, 1H, J=9.8 Hz), 5.65(d, 1H, J=9.8 Hz), 1.41(s, 6H)
1 H NMR (300 MHz, CDCl 3) δ 8.08 (d, 2H, J = 8.9 Hz), 7.34-7.16 (m, 7H), 6.90 (dd, 1H, J = 8.6 Hz, J = 2.5 Hz), 6.82 (d, IH, J = 9.8 Hz), 6.71 (d, IH, J = 9.8 Hz), 6.23 , 6H)
실시예Example 9: (Z)-1-(2,2-디메틸-2H- 9: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )-2-p-) -2-p- 톨릴구아니딘의Tolylguanidine 제조 Produce
1H NMR(300 MHz, CDCl3) δ 8.02(d, 2H, J=8.9 Hz), 7.21(d, 2H, J=8.9 Hz), 7.08(s, 4H), 6.91(dd, 1H, J=8.4 Hz, J=2.4 Hz), 6.84(d, 1H, J=2.4 Hz), 6.66(d, 1H, J=8.4 Hz), 6.21(d, 1H, J=9.9 Hz), 5.63(d, 1H, J=9.9 Hz), 2.27(s, 3H), 1.38(s, 6H); M/S 428.50
1 H NMR (300 MHz, CDCl 3) δ 8.02 (d, 2H, J = 8.9 Hz), 7.21 (d, 2H, J = 8.9 Hz), 7.08 (s, 4H), 6.91 (dd, 1H, J = J = 2.4 Hz), 6.84 (d, 1H, J = 2.4 Hz), 6.66 (d, 1H, J = 8.4 Hz), 6.21 , J = 9.9 Hz), 2.27 (s, 3H), 1.38 (s, 6H); M / S 428.50
실시예Example 10: (Z)-1-(2,2-디메틸-2H- 10: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(3,5--6-yl) -2- (3,5- 디메틸페닐Dimethylphenyl )-3-(4-) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.05(d, 2H, J=8.97 Hz), 7.20(d, 2H, J=8.97 Hz), 6.89(dd, 1H, J=8.46 Hz, J=2.49 Hz), 6.82(d, 1H, J=2.49 Hz), 6.77(s, 3H), 6.69(d, 1H, J =8.46 Hz), 6.22(d, 1H, J=9.83 Hz), 5.64(d, 1H, J=9.83 Hz), 2.24(s, 6H), 1.39(s, 6H); M/S 442.55
1 H NMR (300 MHz, CDCl 3) δ 8.05 (d, 2H, J = 8.97 Hz), 7.20 (d, 2H, J = 8.97 Hz), 6.89 (dd, 1H, J = 8.46 Hz, J = 2.49 Hz 1H), 6.82 (d, IH, J = 2.49 Hz), 6.77 (s, 3H), 6.69 (d, IH, J = 8.46 Hz) , J = 9.83 Hz), 2.24 (s, 6H), 1.39 (s, 6H); M / S 442.55
실시예Example 11: (Z)-1-(2,2-디메틸-2H- 11: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 플루오로페닐Fluorophenyl )-3-(4-) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.10(d, 2H, J=9.0 Hz), 7.26(d, 2H, J=9.0 Hz), 7.17(m, 2H), 6.99(m, 2H), 6.91(dd, 1H, J=8.4 Hz, J=2.4 Hz), 6.81(d, 1H, J=2.4 Hz), 6.73(d, 1H, J=8.4 Hz), 6.24(d, 1H, J=9.9 Hz), 5.66(d, 1H, J=9.9 Hz), 1.42(s, 6H); M/S 432.47
1 H NMR (300 MHz, CDCl 3) δ 8.10 (d, 2H, J = 9.0 Hz), 7.26 (d, 2H, J = 9.0 Hz), 7.17 (m, 2H), 6.99 (m, 2H), 6.91 (d, 1H, J = 8.4 Hz, J = 2.4 Hz), 6.81 (d, 1H, J = 2.4 Hz), 6.73 ), 5.66 (d, 1H, J = 9.9 Hz), 1.42 (s, 6H); M / S 432.47
실시예Example 12: (Z)-2-(4- 12: (Z) -2- (4- 클로로페닐Chlorophenyl )-1-(2,2-디메틸-2H-) -1- (2,2-dimethyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.12(d, 2H, J=7.6 Hz), 7.29-7.14(m, 4H), 7.10(d, 2H, J=8.7 Hz), 6.90(d, 1H, J=2.6 Hz), 6.79-6.71(m, 2H), 6.23(d, 1H, J=9.8 Hz), 5.66(d, 1H, J=9.8 Hz), 1.40(s, 6H); M/S 448.93
1 H NMR (300 MHz, CDCl 3) δ 8.12 (d, 2H, J = 7.6 Hz), 7.29-7.14 (m, 4H), 7.10 (d, 2H, J = 8.7 Hz), 6.90 (d, 1H, J = 2.6 Hz), 6.79-6.71 (m, 2H), 6.23 (d, 1H, J = 9.8 Hz), 5.66 (d, 1H, J = 9.8 Hz), 1.40 (s, 6H); M / S 448.93
실시예Example 13: (Z)-1-(2,2-디메틸-2H- 13: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(2--6-yl) -2- (2- 메톡시페닐Methoxyphenyl )-3-(4-) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.02(d, 2H, J=8.9 Hz), 7.24(d, 2H, J=8.9 Hz), 7.14(d, 2H, J=8.8 Hz), 6.93(dd, 1H, J=8.5 Hz, J=2.3 Hz), 6.86(m, 3H), 6.73(d, 1H, J=8.5 Hz), 6.25(d, 1H, J=9.8 Hz), 5.64(d, 1H, J=9.8 Hz), 3.78(s, 3H), 1.42(s, 6H); M/S 444.50
1 H NMR (300 MHz, CDCl 3) δ 8.02 (d, 2H, J = 8.9 Hz), 7.24 (d, 2H, J = 8.9 Hz), 7.14 (d, 2H, J = 8.8 Hz), 6.93 (dd 1H, J = 8.5 Hz), 6.86 (m, 3H), 6.73 (d, , J = 9.8 Hz), 3.78 (s, 3H), 1.42 (s, 6H); M / S 444.50
실시예Example 14: (Z)-1-(2,2-디메틸-2H- 14: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 메톡시페닐Methoxyphenyl )-3-(4-) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.02(d, 2H, J=8.9 Hz), 7.24(d, 2H, J=8.9 Hz), 7.14(d, 2H, J=8.8 Hz), 6.93(dd, 1H, J=8.5 Hz, J=2.3 Hz), 6.86(m, 3H), 6.73(d, 1H, J=8.5 Hz), 6.25(d, 1H, J=9.8 Hz), 5.64(d, 1H, J=9.8 Hz), 3.78(s, 3H), 1.42(s, 6H); M/S 444.50
1 H NMR (300 MHz, CDCl 3) δ 8.02 (d, 2H, J = 8.9 Hz), 7.24 (d, 2H, J = 8.9 Hz), 7.14 (d, 2H, J = 8.8 Hz), 6.93 (dd 1H, J = 8.5 Hz), 6.86 (m, 3H), 6.73 (d, , J = 9.8 Hz), 3.78 (s, 3H), 1.42 (s, 6H); M / S 444.50
실시예Example 15: (Z)-2-(3,5- 15: (Z) -2- (3,5- 디메톡시페닐Dimethoxyphenyl )-1-(2,2-디메틸-2H-) -1- (2,2-dimethyl-2H- 크로멘Kromen -6-일)-3-(4-니트로페닐)구아니딘의 제조-6-yl) -3- (4-nitrophenyl) guanidine
M/S 474.51
M / S 474.51
실시예Example 16: (Z)-1-(2,2-디메틸-2H- 16: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )-2-(3,4,5-트리메톡시페닐)구아니딘의 제조) -2- (3,4,5-trimethoxyphenyl) guanidine
1H NMR(300 MHz, CDCl3) δ 8.15 (d, J=9.0, 2H), 7.60 (m, 1H), 7.28 (d, J=9.0, 2H), 6.81-6.75 (m, 2H), 7.47 (s, 2H), 6.30 (d, J=10.0, 1H), 5.61 (d, J=10.0, 1H), 3.82 (s, 9H), 1.34 (s, 6H); M/S 504.55
1 H NMR (300 MHz, CDCl 3) δ 8.15 (d, J = 9.0, 2H), 7.60 (m, 1H), 7.28 (d, J = 9.0, 2H), 6.81-6.75 (m, 2H), 7.47 (s, 2H), 6.30 (d, J = 10.0, 1H), 5.61 (d, J = 10.0, 1H), 3.82 (s, 9H), 1.34 (s, 6H); M / S 504.55
실시예Example 17: (Z)-1-(2,2-디메틸-2H- 17: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 플루오로벤질Fluorobenzyl )-3-(4-) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.14(d, 2H, J=8.99 Hz), 7.27(m, 2H), 7.12(d, 2H, J=8.99 Hz), 7.03(m, 2H), 6.85(dd, 1H, J=8.49 Hz, J=2.60 Hz), 6.74(d, 1H, J=2.60 Hz), 6.70(d, 1H, J=8.49 Hz), 6.20(d, 1H, J=9.85 Hz), 5.65(d, 1H, J=9.85 Hz), 4.45(s, 2H), 1.41(s, 6H); M/S 446.49
1 H NMR (300 MHz, CDCl 3) δ 8.14 (d, 2H, J = 8.99 Hz), 7.27 (m, 2H), 7.12 (d, 2H, J = 8.99 Hz), 7.03 (m, 2H), 6.85 (d, 1H, J = 8.49 Hz, J = 2.60 Hz), 6.74 (d, IH, J = 2.60 Hz), 6.70 ), 5.65 (d, 1H, J = 9.85 Hz), 4.45 (s, 2H), 1.41 (s, 6H); M / S 446.49
실시예Example 18: (Z)-1-(2,2-디메틸-2H- 18: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2,3--6-yl) -2,3- 비스(4-니트로페닐)구아니딘의Bis (4-nitrophenyl) guanidine 제조 Produce
1H NMR(300 MHz, CDCl3) δ 8.14(d, 2H, J=9.32 Hz), 8.12(d, 2H, J=8.49 Hz), 6.96(d, 2H, J=8.49 Hz), 6.82(d, 2H, J=9.32 Hz), 6.70(m, 2H), 6.62(s, 1H), 6.22(d, 1H, J=9.81 Hz), 5.66(d, 1H, J=9.81 Hz), 3.55(t, 4H, J=4.11 Hz), 3.45(br-s, 4H), 1.41(s, 6H); M/S 528.55
1 H NMR (300 MHz, CDCl 3) δ 8.14 (d, 2H, J = 9.32 Hz), 8.12 (d, 2H, J = 8.49 Hz), 6.96 (d, 2H, J = 8.49 Hz), 6.82 (d 1H, J = 9.32 Hz), 6.70 (m, 2H), 6.62 (s, , 4H, J = 4.11 Hz), 3.45 (br-s, 4H), 1.41 (s, 6H); M / S 528.55
실시예Example 19: (Z)-1-(2,2-디메틸-2H- 19: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4-(2--6-yl) -2- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)-3-(4-) Piperazin-1-yl) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.10(d, 2H, J=8.7 Hz), 7.06-6.92(m, 4H), 6.88(d, 2H, J=8.7 Hz), 6.74(br-s, 1H), 6.68(d, 1H, J=8.1 Hz), 6.62(br-s, 1H), 6.22(d, 1H, J=9.9 Hz), 5.64(d, 1H, J=9.9 Hz), 3.86(s, 3H), 3.57(t, 4H, J=4.8 Hz), 3.06(br-s, 4H), 1.41(s, 6H); M/S 513.63
1 H NMR (300 MHz, CDCl 3) δ 8.10 (d, 2H, J = 8.7 Hz), 7.06-6.92 (m, 4H), 6.88 (d, 2H, J = 8.7 Hz), 6.74 (br-s, 1H), 6.68 (d, 1H, J = 8.1 Hz), 6.62 (br-s, s, 3H), 3.57 (t, 4H, J = 4.8 Hz), 3.06 (br-s, 4H), 1.41 (s, 6H); M / S 513.63
실시예Example 20: (Z)-1-(2,2-디메틸-2H- 20: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4-(3--6-yl) -2- (4- (3- 메톡시페닐Methoxyphenyl )피페라진-1-일)-3-(4-) Piperazin-1-yl) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.08(d, 2H, J=8.40 Hz), 7.18(m, 1H), 6.93(d, 2H, J=8.4 Hz), 6.75(br-s, 1H), 6.67(d, 1H, J=8.40 Hz), 6.63(br-s, 1H), 6.53(d, 1H, J=9.03 Hz), 6.45(m, 2H), 6.21(d, 1H, J=9.78 Hz), 5.64(d, 1H, J=9.78 Hz), 3.79(s, 3H), 3.52(t, 4H, J=4.91 Hz), 3.17(br-s, 4H), 1.41(s, 6H); M/S 513.64
1 H NMR (300 MHz, CDCl 3) δ 8.08 (d, 2H, J = 8.40 Hz), 7.18 (m, 1H), 6.93 (d, 2H, J = 8.4 Hz), 6.75 (br-s, 1H) , 6.67 (d, IH, J = 8.40 Hz), 6.63 (br-s, (S, 3H), 3.52 (t, 4H, J = 4.91 Hz), 3.17 (br-s, 4H), 1.41 (s, 6H); 5.64 (d, 1H, J = 9.78 Hz). M / S 513.64
실시예Example 21: (Z)-1-(2,2-디메틸-2H- 21: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-(4-(4--6-yl) -2- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-3-(4-) Piperazin-1-yl) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.11(d, 2H, J=9.0 Hz), 7.03-6.95(m, 3H), 6.91-6.85(m, 2H), 6.74(br-s, 1H), 6.69(d, 1H, J=8.1 Hz), 6.62(br-s, 1H), 6.22(d, 1H, J=9.9 Hz), 5.65(d, 1H, J=9.9 Hz), 3.53(t, 4H, J=5.0 Hz), 3.09(br-s, 4H), 1.41(s, 6H); M/S 501.58
1 H NMR (300 MHz, CDCl 3) δ 8.11 (d, 2H, J = 9.0 Hz), 7.03-6.95 (m, 3H), 6.91-6.85 (m, 2H), 6.74 (br-s, 1H), J = 9.9 Hz), 3.53 (t, 4H), 6.62 (d, 1H, J = , J = 5.0 Hz), 3.09 (br-s, 4H), 1.41 (s, 6H); M / S 501.58
실시예Example 22: (Z)-2-(4-(4- 22: (Z) -2- (4- (4- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(2,2-디메틸-2H-) Piperazin-1-yl) -1- (2,2-dimethyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.10(d, 2H, J=8.7 Hz), 7.22(d, 2H, J=7.5 Hz), 6.94(d, 2H, J=8.7 Hz), 6.83(d, 2H, J=7.5 Hz), 6.75(br-s, 1H), 6.68(d, 1H, J=8.4 Hz), 6.62(br-s, 1H), 6.21(d, 1H, J=9.9 Hz), 5.64(d, 1H, J=9.9 Hz), 3.52(t, 4H, J=5.3 Hz), 3.13(br-s, 4H), 1.41(s, 6H); M/S 518.03
1 H NMR (300 MHz, CDCl 3) δ 8.10 (d, 2H, J = 8.7 Hz), 7.22 (d, 2H, J = 7.5 Hz), 6.94 (d, 2H, J = 8.7 Hz), 6.83 (d 1H, J = 8.9 Hz), 6.62 (br-s, 1H), 6.21 (d, , 5.64 (d, 1H, J = 9.9 Hz), 3.52 (t, 4H, J = 5.3 Hz), 3.13 (br-s, 4H), 1.41 (s, 6H); M / S 518.03
실시예Example 23: (Z)-1-(2,2-디메틸-2H- 23: (Z) -1- (2,2-Dimethyl-2H- 크로멘Kromen -6-일)-2-((3,4--6-yl) -2 - ((3,4- 디옥소사이클로헥사Dioxocyclohexa -1,5-디에닐)-1,5-dienyl) 메틸methyl )-3-(4-) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.14(d, 2H, J=8.9 Hz), 7.16(d, 2H, J=8.9 Hz), 6.87(dd, 1H, J=8.5 Hz, J=2.5 Hz), 6.81-6.76(m, 4H), 6.70(d, 1H, J=8.5 Hz), 6.21(d, 1H, J=9.8 Hz), 5.96(s, 2H), 5.64(d, 1H, J=9.8 Hz), 4.42(s, 2H), 1.40(s, 6H); M/S 472.51
1 H NMR (300 MHz, CDCl 3) δ 8.14 (d, 2H, J = 8.9 Hz), 7.16 (d, 2H, J = 8.9 Hz), 6.87 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz 1H), 6.81-6.76 (m, 4H), 6.70 (d, IH, J = 8.5 Hz), 6.21 9.8 Hz), 4.42 (s, 2H), 1.40 (s, 6H); M / S 472.51
실시예Example 24: (Z)-1-(2,7-디메틸-2-프로필-2H- 24: (Z) -1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )-2-페) -2- 닐구아니딘Nile Guanidine 의 제조Manufacturing
1H NMR(300 MHz, CDCl3) δ 8.13(d, 2H), 7.33-7.23(m, 7H), 7.10(t, 1H), 6.82(s, 1H), 6.65(s, 1H), 6.27(d, 1H), 5.56(d, 1H), 5.64(d, 1H, J=9.8 Hz), 2.20(s, 3H), 1.62(m, 2H), 1.46(m, 2H), 1.37(s, 3H), 0.92(t, 3H); M/S 456.54
1 H NMR (300 MHz, CDCl 3) δ 8.13 (d, 2H), 7.33-7.23 (m, 7H), 7.10 (t, 1H), 6.82 (s, 1H), 6.65 (s, 1H), 6.27 ( (d, IH), 5.56 (d, IH), 5.64 (d, IH, J = 9.8 Hz), 2.20 (s, 3H), 1.62 (m, 2H) ), 0.92 (t, 3 H); M / S 456.54
실시예Example 25: (Z)-1-(2,7-디메틸-2-프로필-2H- 25: (Z) -1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )-2-p-톨) -2-p-Tol 릴구아니Ruguzi 딘의 제조Manufacture of Dean
1H NMR(300 MHz, CDCl3) δ 8.06(d, 2H), 7.22(d, 2H), 7.05(m, 4H), 6.82(s, 1H), 6.59(s, 1H), 6.25(d, 1H), 5.54(d, 1H), 2.28(s, 3H), 2.04(s, 3H), 1.64(m, 2H), 1.58(m, 2H), 1.37(s, 3H), 0.90(t, 3H); M/S 470.58
1 H NMR (300 MHz, CDCl 3) δ 8.06 (d, 2H), 7.22 (d, 2H), 7.05 (m, 4H), 6.82 (s, 1H), 6.59 (s, 1H), 6.25 (d, 3H), 1.64 (s, 3H), 1.64 (m, 2H), 1.58 (m, 2H), 1.37 ); M / S 470.58
실시예Example 26: (Z)-1-(2,7-디메틸-2-프로필-2H- 26: (Z) -1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-2-(2--6-yl) -2- (2- 메톡시페닐Methoxyphenyl )-3-(4-니) -3- (4- 트로TRO 페닐)구아니딘의 제조Phenyl) guanidine < / RTI >
M/S 486.56
M / S 486.56
실시예Example 27: (Z)-1-(2,7-디메틸-2-프로필-2H- 27: (Z) -1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 메톡시페닐Methoxyphenyl )-3-(4-니) -3- (4- 트로TRO 페닐)구아니딘의 제조Phenyl) guanidine < / RTI >
1H NMR(300 MHz, CDCl3) δ 8.10(d, 2H), 7.28(d, 2H), 7.15(d, 2H), 6.86(m, 3H), 6.62(s, 1H), 6.26(d, 1H), 5.55(d, 1H), 3.78(s, 3H), 2.20(s, 3H), 1.66(m, 2H), 1.60(m, 2H), 1.40(s, 3H), 0.91(t, 3H); M/S 486.56
1 H NMR (300 MHz, CDCl 3) δ 8.10 (d, 2H), 7.28 (d, 2H), 7.15 (d, 2H), 6.86 (m, 3H), 6.62 (s, 1H), 6.26 (d, 2H), 1.40 (s, 3H), 0.91 (t, 3H), 1.60 (m, ); M / S 486.56
실시예Example 28: (Z)-2-(3,5- 28: (Z) -2- (3,5- 디메톡시페닐Dimethoxyphenyl )-1-(2,7-디메틸-2-프로필-2H-) -1- (2,7-dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
M/S 516.57
M / S 516.57
실시예Example 29: (Z)-1-(2,7-디메틸-2-프로필-2H- 29: (Z) -1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-3-(4--6-yl) -3- (4- 니트로페닐Nitrophenyl )-2-(3,4,5-트) -2- (3,4,5-tri 리메Rime 톡시페닐)구아니딘의 제조Ethoxyphenyl) guanidine < / RTI >
M/S 546.58
M / S 546.58
실시예Example 30: (Z)-1-(2,7-디메틸-2-프로필-2H- 30: (Z) -1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-2-(4--6-yl) -2- (4- 플루오로페닐Fluorophenyl )-3-(4-) -3- (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(500 MHz, CDCl3) δ 8.10(d, 2H), 7.26(d, 2H), 7.16(m, 2H), 6.80(s, 1H), 6.98(t, 2H), 6.80(s, 1H), 6.61(s, 1H), 6.25(d, 1H), 5.55(d, 1H), 2.20(s, 3H), 1.65(m, 2H), 1.41(m, 2H), 1.35(s, 3H), 0.91(t, 3H, J=7.30 Hz); M/S 474.52
1 H NMR (500 MHz, CDCl 3) δ 8.10 (d, 2H), 7.26 (d, 2H), 7.16 (m, 2H), 6.80 (s, 1H), 6.98 (t, 2H), 6.80 (s, 2H), 1.41 (m, 2H), 1.35 (s, 3H), 6.65 (d, IH) ), 0.91 (t, 3H, J = 7.30 Hz); M / S 474.52
실시예Example 31: (Z)-1-(2,7-디메틸-2-프로필-2H- 31: (Z) -1- (2,7-Dimethyl-2-propyl-2H- 크로멘Kromen -6-일)-2,3-비스(4--6-yl) -2,3-bis (4- 니트로페닐Nitrophenyl )구아니딘의 제조) Preparation of guanidine
1H NMR(300 MHz, CDCl3) δ 8.18(d, 4H, J=9.2 Hz), 7.53(d, 2H, J=9.2 Hz), 7.40(br-s, 2H), 6.83(s, 1H), 6.67(s, 1H), 6.27(d, 1H, J=9.9 Hz), 5.59(d, 1H, J=9.9 Hz), 2.22(s, 3H), 1.62-1.43(m, 4H), 1.38(s, 3H), 0.93(m, 3H); M/S 501.55
1 H NMR (300 MHz, CDCl 3) δ 8.18 (d, 4H, J = 9.2 Hz), 7.53 (d, 2H, J = 9.2 Hz), 7.40 (br-s, 2H), 6.83 (s, 1H) , 6.67 (s, 1H), 6.27 (d, 1H, J = 9.9 Hz), 5.59 (d, 1H, J = 9.9 Hz), 2.22 s, 3H), 0.93 (m, 3H); M / S 501.55
실험예Experimental Example : 생물검정실험: Biological assay
1) GSNO 리덕타아제의 활성 측정 방법 설계1) Design method of activity measurement of GSNO reductase
GSNO 리덕타아제는 GSNO를 환원시키며, 이 과정에서 조효소 NAD의 환원형인 NADH가 산화되어 NAD+로 전환된다. NADH 농도는 흡광도 340 nm에서 측정할 수 있으며, GSNO 리덕타아제의 효소 활성은 흡광도 340 nm에서 일정 시간 간격으로 NADH 농도를 측정함으로써 얻을 수 있다.
GSNO reductase reduces GSNO and NADH, which is a reduced form of coenzyme NAD, is oxidized and converted to NAD +. The NADH concentration can be measured at 340 nm absorbance and the enzyme activity of GSNO reductase can be obtained by measuring the NADH concentration at a constant time interval of 340 nm absorbance.
사용한 모든 시약들은 100 μM의 염화아연을 포함하는 100 mM의 인산나트륨 완충액에 희석시켜 사용하였다. 측정 방법은 96-웰 플레이트에서 800 nM의 GSNO 리덕타아제 25 ㎕와 8% DMSO 용액 25 ㎕를 혼합하여 30℃에서 10분 동안 반응시킨 후, 미리 혼합해 놓은 기질 용액(1 mM의 GSNO, 0.5 mM의 NADH) 50 ㎕를 첨가하였다. 그 후, 340 nm에서의 흡광도를 3분 동안 20초 간격으로 측정하여, Vmax 값을 획득하였다. 이와 같이 획득한 값은 Flexstation SoftMax pro 소프트웨어(Molecular device)의 Kinetics를 이용하여, Vmax 값을 계산하였다.
All reagents used were diluted in 100 mM sodium phosphate buffer containing 100 μM zinc chloride. For the measurement, 25 μl of 800 nM GSNO reductase and 25 μl of 8% DMSO solution were mixed in a 96-well plate, and reacted at 30 ° C for 10 minutes. Subsequently, a premixed substrate solution (1 mM GSNO, 0.5 mM NADH) were added. Thereafter, the absorbance at 340 nm was measured at intervals of 20 seconds for 3 minutes to obtain a Vmax value. The value thus obtained by using the Kinetics of pro Flexstation SoftMax software (Molecular device), and calculated the V max value.
본 실험의 양성 대조군으로서, GSNO 리덕타아제의 활성을 억제하는 것으로 알려져 있는 N6022 화합물 1μM을 사용하였다. 상기 N6022 화합물의 화학식은 다음과 같다.As a positive control for this experiment, 1 mu M of N6022 compound known to inhibit the activity of GSNO reductase was used. The chemical formula of the N6022 compound is as follows.
음성 대조군(DMSO)의 Vmax 값과 비교하여, N6022에 의해 GSNO 리덕타아제의 활성이 억제되는 정도를 측정하였다 (도 1c).
Compared to the V max value of the negative control (DMSO), it was measured by the degree to which N6022 inhibited the activity of the Li GSNO reductase kinase (Fig. 1c).
2) 화합물에 의한 GSNO 리덕타아제의 활성 억제 효과의 측정2) Measurement of inhibitory effect of GSNO reductase on compound activity
본 실험에서는, 본 발명에 따른 화합물이 GSNO 리덕타아제의 활성을 억제할 수 있는지를 확인하였다. 96-웰 플레이트에서 800 nM의 GSNO 리덕타아제 25 ㎕와 40 uM(DMSO 8%)의 화합물 25 ㎕를 혼합하여 30℃에서 10분 동안 반응시킨 후, 미리 혼합해 놓은 기질 용액(1 mM의 GSNO, 0.5 mM의 NADH) 50 ㎕를 첨가하였다. 그 후, 340 nm에서의 흡광도를 3분 동안 20초 간격으로 측정하여 Vmax 값을 얻었다. 시료 용액의 대조군은 화합물과 동일한 농도의 DMSO(최종 2%)를 사용하였으며, 이때 획득한 측정값을 100으로 정하였다. 80% 이상의 GSNO 리덕타아제 활성 저해 효과를 나타내는 추출물을 유효 화합물로 선택하였고, 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 대표하는 몇몇 화합물에 대한 GSNOR 활성저해 실험결과를 다음 표 1에 나타내었다.In this experiment, it was confirmed whether the compound according to the present invention can inhibit the activity of GSNO reductase. 25 μl of 800 nM GSNO reductase in a 96-well plate and 25 μl of a compound of 40 uM (DMSO 8%) were mixed and reacted at 30 ° C for 10 minutes. Subsequently, the premixed substrate solution (1 mM GSNO , 0.5 mM NADH) were added. Thereafter, the absorbance at 340 nm was measured at intervals of 20 seconds for 3 minutes to obtain a V max value. As a control group of the sample solution, DMSO (final 2%) at the same concentration as the compound was used, and the obtained measurement value was set at 100. An extract showing 80% or more inhibitory activity of GSNO reductase activity was selected as an effective compound, and the results of GSNOR inhibition experiments for several compounds represented by the formula 1 according to the present invention are shown in the following Table 1 .
(IC50, μM)GSNOR inhibitory effect
(IC 50 , uM)
(IC50, μM)GSNOR inhibitory effect
(IC 50 , uM)
다음은 본 발명에 따른 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
The following are illustrative of some formulations containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.
제제 1: 정제(직접 가압)Formulation 1: Tablets (direct pressurization)
활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.
제제 2: 정제(습식 조립)Formulation 2: Tablet (wet assembly)
활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.
제제 3: 분말과 Formulation 3: Powder and 캡슐제Capsule
활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.
5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.
제제 4: 주사제Formulation 4: Injection
활성성분 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.Injections were prepared by containing 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.
Claims (8)
[화학식 1]
상기 식에서,
R1은 비치환되거나 또는 니트로로 치환된 페닐이고,
R2는 3,4-디옥소-벤질, 4-페닐-피페라진-1-일, 벤질 또는 페닐이고, 여기서 상기 R2는 비치환되거나 또는 C1 -4 알킬, C1 -4 알콕시, 할로겐 및 니트로로 구성되는 군으로부터 선택되는 1개 내지 3개의 치환기로 치환되고,
R3는 수소 또는 C1 -4 알킬이고, 및
R4는 수소 또는 C1 -4 알킬이다.
A pharmaceutical composition for preventing or treating asthma or inflammatory diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
In this formula,
R < 1 > is phenyl unsubstituted or substituted by nitro,
R 2 is 3,4-dioxo-benzyl, 4-phenyl-piperazin-1-yl, benzyl or phenyl, wherein R 2 is unsubstituted or C 1 -4 alkyl, C 1 -4 alkoxy, halogen ≪ / RTI > and nitro, and < RTI ID = 0.0 >
R 3 is hydrogen or C 1 -4 alkyl, and
R 4 is hydrogen or C 1 -4 alkyl.
2. A pharmaceutical composition according to claim 1, wherein R < 1 > is phenyl or 4-nitrophenyl.
2. The compound of claim 1 wherein R < 2 > is 3,4-dioxo-benzyl; A C 1 -4 alkoxy or halogen substituted 4-phenyl-piperazin-1-yl; Benzyl substituted with halogen; Or unsubstituted or C 1 -4 alkyl, C 1 -4 alkoxy, halogen, and characterized in that the phenyl substituted with one to three substituents selected from the group consisting of nitro, a pharmaceutical composition.
A compound according to claim 3, wherein R 2 is selected from the group consisting of 3,4-dioxo-benzyl, 4- (2-methoxyphenyl) piperazin- Phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2- (4-fluorophenyl) Methoxyphenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, or 4-nitro Lt; RTI ID = 0.0 > phenyl. ≪ / RTI >
2. The pharmaceutical composition according to claim 1, wherein R < 3 > is hydrogen or methyl.
2. The pharmaceutical composition according to claim 1, wherein R < 4 > is hydrogen or ethyl.
The pharmaceutical composition according to claim 1, wherein R 3 is hydrogen and R 4 is hydrogen, or R 3 is methyl and R 4 is ethyl.
1) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-니트로페닐)-3-페닐구아니딘,
2) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2,3-디페닐구아니딘,
3) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-플루오로페닐)-3-페닐구아니딘,
4) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(2-메톡시페닐)-3-페닐구아니딘,
5) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-메톡시페닐)-3-페닐구아니딘,
6) (Z)-2-(3,5-디메톡시페닐)-1-(2,2-디메틸-2H-크로멘-6-일)-3-페닐구아니딘,
7) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-페닐-2-(3,4,5-트리메톡시페닐)구아니딘,
8) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)-2-페닐구아니딘,
9) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)-2-p-톨릴구아니딘,
10) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(3,5-디메틸페닐)-3-(4-니트로페닐)구아니딘,
11) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-플루오로페닐)-3-(4-니트로페닐)구아니딘,
12) (Z)-2-(4-클로로페닐)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,
13) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(2-메톡시페닐)-3-(4-니트로페닐)구아니딘,
14) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-메톡시페닐)-3-(4-니트로페닐)구아니딘,
15) (Z)-2-(3,5-디메톡시페닐)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,
16) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)-2-(3,4,5-트리메톡시페닐)구아니딘,
17) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-플루오로벤질)-3-(4-니트로페닐)구아니딘,
18) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2,3-비스(4-니트로페닐)구아니딘,
19) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-(2-메톡시페닐)피페라진-1-일)-3-(4-니트로페닐)구아니딘,
20) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-(3-메톡시페닐)피페라진-1-일)-3-(4-니트로페닐)구아니딘,
21) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-(4-(4-플루오로페닐)피페라진-1-일)-3-(4-니트로페닐)구아니딘,
22) (Z)-2-(4-(4-클로로페닐)피페라진-1-일)-1-(2,2-디메틸-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,
23) (Z)-1-(2,2-디메틸-2H-크로멘-6-일)-2-((3,4-디옥소사이클로헥사-1,5-디에닐)메틸)-3-(4-니트로페닐)구아니딘,
24) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)-2-페닐구아니딘,
25) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)-2-p-톨릴구아니딘,
26) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2-(2-메톡시페닐)-3-(4-니트로페닐)구아니딘,
27) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2-(4-메톡시페닐)-3-(4-니트로페닐)구아니딘,
28) (Z)-2-(3,5-디메톡시페닐)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)구아니딘,
29) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-3-(4-니트로페닐)-2-(3,4,5-트리메톡시페닐)구아니딘,
30) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2-(4-플루오로페닐)-3-(4-니트로페닐)구아니딘, 및
31) (Z)-1-(2,7-디메틸-2-프로필-2H-크로멘-6-일)-2,3-비스(4-니트로페닐)구아니딘
으로 구성되는 군으로부터 선택되는 것을 특징으로 하는, 약학적 조성물.The compound according to claim 1, wherein the compound is
1) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-nitrophenyl)
2) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2,3-diphenylguanidine,
3) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-fluorophenyl)
4) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (2-methoxyphenyl)
5) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-methoxyphenyl)
6) Synthesis of (Z) -2- (3,5-dimethoxyphenyl) -1- (2,2-dimethyl-2H-chromen-
7) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -3-phenyl-2- (3,4,5-trimethoxyphenyl) guanidine,
8) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2- phenylguanidine,
9) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2-
10) (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (3,5- dimethylphenyl) -3- (4-nitrophenyl) guanidine,
11) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-fluorophenyl) -3-
12) Synthesis of (Z) -2- (4-chlorophenyl) -1- (2,2-dimethyl-2H-chromen-
13) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (2-methoxyphenyl) -3-
14) Synthesis of (Z) -1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4-methoxyphenyl) -3-
15) Synthesis of (Z) -2- (3,5-dimethoxyphenyl) -1- (2,2-dimethyl-2H-chromen-
16) Synthesis of (Z) -l- (2,2-dimethyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2- (3,4,5-trimethoxyphenyl) guanidine,
17) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2- (4- fluorobenzyl) -3- (4-nitrophenyl) guanidine,
18) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2,3-bis (4-nitrophenyl) guanidine,
1- (2,2-dimethyl-2H-chromen-6-yl) -2- (4- (2- methoxyphenyl) piperazin- Nitrophenyl) guanidine,
2- (4- (3-methoxyphenyl) piperazin-1 -yl) -3- (4- Nitrophenyl) guanidine,
21) (Z) -1- (2,2-Dimethyl-2H-chromen-6-yl) -2- (4- (4- fluorophenyl) piperazin- Nitrophenyl) guanidine,
22) (Z) -2- (4- (4-Chlorophenyl) piperazin-1-yl) Phenyl) guanidine,
Dimethyl-2H-chromen-6-yl) -2 - ((3,4-dioxocyclohexa-1,5-dienyl) methyl) -3- (4-nitrophenyl) guanidine,
24) (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-
25) Synthesis of (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -3- (4-nitrophenyl) -2-
26) Synthesis of (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2- (2-methoxyphenyl) -3-
27) Synthesis of (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2- (4-methoxyphenyl) -3-
28) Synthesis of (Z) -2- (3,5-dimethoxyphenyl) -1- (2,7-dimethyl- ,
29) (Z) -1- (2,7-Dimethyl-2-propyl-2H-chromen- Phenyl) guanidine,
30) (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2- (4-fluorophenyl) -3-
31) (Z) -1- (2,7-dimethyl-2-propyl-2H-chromen-6-yl) -2,3-bis (4-nitrophenyl) guanidine
≪ / RTI > or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020130120831A KR101540085B1 (en) | 2013-10-10 | 2013-10-10 | Pharmaceutical composition comprising N-(2,2’-disubstituted-2H-cromene-6-yl)-N’,N”-disubstituted-guanidine derivatives for treating or preventing asthma or inflammation disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020130120831A KR101540085B1 (en) | 2013-10-10 | 2013-10-10 | Pharmaceutical composition comprising N-(2,2’-disubstituted-2H-cromene-6-yl)-N’,N”-disubstituted-guanidine derivatives for treating or preventing asthma or inflammation disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20150042078A true KR20150042078A (en) | 2015-04-20 |
| KR101540085B1 KR101540085B1 (en) | 2015-07-28 |
Family
ID=53035329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020130120831A KR101540085B1 (en) | 2013-10-10 | 2013-10-10 | Pharmaceutical composition comprising N-(2,2’-disubstituted-2H-cromene-6-yl)-N’,N”-disubstituted-guanidine derivatives for treating or preventing asthma or inflammation disease |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101540085B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102091464B1 (en) | 2019-08-30 | 2020-03-20 | (주)오스티오뉴로젠 | Composition for anti-inflammation |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101127158B1 (en) * | 2004-12-31 | 2012-03-20 | 한국화학연구원 | Derivatives of N-2,2-disubstituted- 2H-cromene-6-yl-N,N'-disubstituted guanidine derivatives for treating hepatic fibrosis and cirrhosis |
| KR101086456B1 (en) * | 2009-10-15 | 2011-11-25 | 한국원자력의학원 | Composition for inhibiting TGF-? comprising imidazopurine derivatives |
-
2013
- 2013-10-10 KR KR1020130120831A patent/KR101540085B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR101540085B1 (en) | 2015-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69815317T2 (en) | PYRROLO [2,3-D] PYRIMIDINE AND ITS USE AS TYROSINE KINASE INHIBITORS | |
| FR2823209A1 (en) | NEW THIOHYDANTOINS AND THEIR USE IN THERAPEUTICS | |
| WO2010069684A1 (en) | Compounds for treatment of duchenne muscular dystrophy | |
| JP2009242437A (en) | Sulfonamide derivative | |
| US9273005B2 (en) | Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases | |
| JP2005089334A (en) | 8-hydroxyadenine compound | |
| US7985754B2 (en) | Selective antagonists of A2A adenosine receptors | |
| JPS6339866A (en) | N-n-di-substituted-omega-(2-amino-3-(carbonylmethyl)-3, 4-dihydroquinoazolinyl) oxyalkylamide | |
| JP2023182589A (en) | Pharmaceutical composition containing phenylsulfonamide, and therapeutic application of the same | |
| KR100704009B1 (en) | 6-Alkylamino-2-methyl-2'-N-methyl substituted sulfonamidomethyl-2H-1-benzopyran derivatives as anti-inflammatory inhibitors | |
| KR101540085B1 (en) | Pharmaceutical composition comprising N-(2,2’-disubstituted-2H-cromene-6-yl)-N’,N”-disubstituted-guanidine derivatives for treating or preventing asthma or inflammation disease | |
| FR2593818A1 (en) | ACYLAMINOMETHYL-3 IMIDAZO (1,2-A) PYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE | |
| WO2019042442A1 (en) | Compound having tyrosine protein kinase jak1- or jak2-inhibittion and degradation activity | |
| JP4336299B2 (en) | 6-alkylamino-2,2'-double-substituted-7,8-double-substituted-2H-1-benzopyran derivatives having 5-lipoxygenase inhibitory activity | |
| US20220274922A1 (en) | Sulfone compounds and pharmaceutical compositions thereof, and their therapeutic applications | |
| KR101135574B1 (en) | Derivatives of N-2,2-disubstituted-2H-cromene-6-yl thiourea for treating hepatic fibrosis and cirrhosis | |
| US10233153B2 (en) | Pyridinethiones, pharmaceutical compositions thereof, and their therapeutic use for treating a proliferative, inflammatory, neurodegenerative, or immune-mediated disease | |
| WO2020177752A1 (en) | 1,2,4-triazole compound, preparation method therefor and pharmaceutical use thereof | |
| CN116082239A (en) | PDE4/7 double-target inhibitor and preparation method and application thereof | |
| CS228531B2 (en) | Method for the production of phenylpiperazine derivates | |
| KR100508156B1 (en) | Cathechol Hydrazide Derivatives | |
| RU2565667C1 (en) | 2-aryl-substituted n-arylimidazolines, selective cyclooxygenase-2 inhibitors, methods for production and use thereof | |
| CN116535361A (en) | Substituted hydroxypyrimidine xanthine oxidase inhibitor and preparation method and pharmaceutical application thereof | |
| JPH01216980A (en) | Alkyl-pyperadinyl-5, 6-alkylene pyrimidines | |
| JP2024515062A (en) | Deuterated DHODH inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| LAPS | Lapse due to unpaid annual fee |