KR840002087B1 - Process for preparing sulfonylureas - Google Patents

Process for preparing sulfonylureas Download PDF

Info

Publication number
KR840002087B1
KR840002087B1 KR1019840005313A KR840005313A KR840002087B1 KR 840002087 B1 KR840002087 B1 KR 840002087B1 KR 1019840005313 A KR1019840005313 A KR 1019840005313A KR 840005313 A KR840005313 A KR 840005313A KR 840002087 B1 KR840002087 B1 KR 840002087B1
Authority
KR
South Korea
Prior art keywords
ethyl
oxo
methyl
carboxamido
melting point
Prior art date
Application number
KR1019840005313A
Other languages
Korean (ko)
Inventor
베이어 루디
히트젤 볼케르
게이센 칼
레지쯔 귄테르
Original Assignee
훽스트 아크티엔 게젤샤프트
베른하르트 벡, 하인리히 벡커
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 훽스트 아크티엔 게젤샤프트, 베른하르트 벡, 하인리히 벡커 filed Critical 훽스트 아크티엔 게젤샤프트
Priority to KR1019840005313A priority Critical patent/KR840002087B1/en
Application granted granted Critical
Publication of KR840002087B1 publication Critical patent/KR840002087B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C07D223/10—Oxygen atoms attached in position 2

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Sulfonylureas of formula (I) and their salts were newly prepd. by reacting benzene sulfinic acids of formula (II) or their alkali metal salts with N-R1-N'-hydroxyureas in the presence of benzene sulfinic acid halide or an acidic condensing agent. In the formulas X is C3-6 alkylene or alkenylene; Y is C2-3 alkylene; and R1 is C4-6 alkyl, cycloalkyl, alkylcycloalkyl, dialkylcycloalkyl, cycloalkylalkyl, C4-9 cycloalkenyl, methyl cyclopentylmethyl, cyclohexenyl methyl, etc. The prods. are used in the treatment of diabetes mellitus by lowering blood sugar levels.

Description

설포닐 우레아의 제조방법Method for preparing sulfonyl urea

본 발명은 혈당 강하제로 사용할 수 있는 일반식(I)의 설포닐 우레아 및 생리학적으로 무독한 그의 염의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of sulfonyl urea of formula (I) and physiologically toxic salts thereof, which can be used as blood sugar lowering agents.

Figure kpo00001
Figure kpo00001

상기 식에서 X는 각각 탄소수 1내지 4의 알킬그룹 3개까지로 임의 치환된 탄소수 3내지 6의 알킬렌 또는 알케닐렌 이거나,Wherein X is alkylene or alkenylene of 3 to 6 carbon atoms optionally substituted with up to 3 alkyl groups of 1 to 4 carbon atoms, or

Figure kpo00002
Figure kpo00002

의 비사이클 시스템이고 ;A bicyclic system of;

Y는 탄소수 2내지 3의 알킬렌이며,Y is C2-C3 alkylene,

R1을 탄소수 4내지 6의 알킬, 사이클로알킬, 알킬사이클로알킬, 디알킬사이클로알킬, 사이클로알킬알킬, 탄소수 4내지 9의 사이클로알케닐 또는 알킬 사이클로알케닐, 메틸 사이클로펜틸메틸, 사이클로헥실닐메틸, 클로로사이클로헥실, 메톡시 사이클로헥실, 비사이클로헵틸, 비사이클로헵테닐, 비사이클로헵틸메틸, 비사이클로헵테메틸, 비사이클로옥틸, 노르트리사이크릴, 아다맨틸 또는 벤질이다.R 1 is alkyl of 4 to 6 carbon atoms, cycloalkyl, alkylcycloalkyl, dialkylcycloalkyl, cycloalkylalkyl, cycloalkenyl or alkyl cycloalkenyl of 4 to 9 carbon atoms, methyl cyclopentylmethyl, cyclohexylylmethyl, Chlorocyclohexyl, methoxy cyclohexyl, bicycloheptyl, bicycloheptenyl, bicycloheptylmethyl, bicycloheptemethyl, bicyclooctyl, nortricyclyl, adamantyl or benzyl.

상기 식에서 X는 탄소수 3내지 4이며 탄소수 1내지 2의 알킬그룹 1내지 2개로 치환된 알킬렌 또는 알케닐렌 래디칼이 바람직하고, Y는 -CH2-CH2- 또는 -

Figure kpo00003
특히 -CH2-CH2-가 바람직하다.In the above formula, X is 3 to 4 carbon atoms and alkylene or alkenylene radicals substituted with 1 to 2 alkyl groups of 1 to 2 carbon atoms are preferable, and Y is -CH 2 -CH 2 -or-
Figure kpo00003
Especially -CH 2 -CH 2 -is preferable.

R1을 메틸 사이클로펜틸, 사이클로펜틸 메틸, 사이클로헥실, 4-메틸-, 4-에틸-, 또는 4-이소프로필사이클로헥실이 바람직하다.Preference is given to R 1 as methyl cyclopentyl, cyclopentyl methyl, cyclohexyl, 4-methyl-, 4-ethyl-, or 4-isopropylcyclohexyl.

사용 가능한 비사이클 래디칼은 다음과 같다. 비사이클로[2.2.1]휨틸, 비사이클로[2.2.1]헵틸메틸 및 상응하는 불포화 래디칼과 비사이클로[2.2.2]옥틸 래디칼.Bicyclic radicals that can be used are as follows. Bicyclo [2.2.1] boltyl, bicyclo [2.2.1] heptylmethyl and the corresponding unsaturated radicals and bicyclo [2.2.2] octyl radicals.

본 발명은 일반식(I)의 설포닐 우레아의 제조방법에 관한 것으로 그들을 함유하거나 그들로 구성된 약학적 제제 및 당뇨병 치료제로서의 그들의 용도도 포함한다. 본 발명의 일반식(I) 화합물은 상응하게 치환된 벤젠 설포닐 할라이드를 R1-치환된 우레아 또는 그의 알카리 금속염과 반응시키거나, 상응하는 치환된 벤젠설핀산 할라이드, 또는 산성 축합제의 존재하에 상응하는 치환된 설핀산 또는 그의 알카리 금속염을 N-R1-N'-하이드록시 우레아와 반응시키고, 필요시 반응 생성물을 알카리제로 처리하여 염을 제조하는 방법으로 제조한다.The present invention relates to a method for preparing sulfonyl urea of general formula (I) and includes pharmaceutical preparations containing or consisting of them and their use as therapeutic agents for diabetes. The general formula (I) compound of the present invention reacts a correspondingly substituted benzene sulfonyl halide with R 1 -substituted urea or an alkali metal salt thereof, or in the presence of a corresponding substituted benzenesulfinic acid halide, or acidic condensing agent. The corresponding substituted sulfinic acid or an alkali metal salt thereof is reacted with NR 1 -N′-hydroxy urea and, if necessary, prepared by a process for preparing the salts by treatment with an alkaline agent.

제조방법에 따른 설포닐 할라이드 및 설피닐 할라이드로는 특히 클로라이드가 적당하다. 티오닐 클로라이드 또는 다중인산은 산성 축합제로 사용할 수 있다.Chloride is particularly suitable as sulfonyl halide and sulfinyl halide according to the preparation method. Thionyl chloride or polyphosphoric acid can be used as the acid condensing agent.

생리적으로 무독한 염은 기지의 방법으로 제조한다. 염의 생성에는 특히 알카리금속 수산화물, 탄산염 또는 중탄산염 및 알카리토금속 수산화물, 탄산염 또는 중탄산염과 생리적으로 무독한 유기염기가 적절하다.Physiologically nontoxic salts are prepared by known methods. Particularly suitable for the production of salts are alkali metal hydroxides, carbonates or bicarbonates and alkaline earth metal hydroxides, carbonates or bicarbonates and physiologically toxic organic bases.

본 발명에 따른 제조 방법의 태양은 반응 조건에 따라 변화시킬 수 있다. 예를 들어, 반응은 용매의 존재하에서나 부재하에서, 실온 또는 승온에서 진행시킬 수 있다.Aspects of the production process according to the invention can be varied depending on the reaction conditions. For example, the reaction can proceed at room temperature or elevated temperature, in the presence or absence of a solvent.

출발물질의 특성에 따라, 상술한 제조방법중 어떤 방법으로는 목적하는 벤젠설포닐 우레아의 수율이 낮거나, 본 화합물을 합성하는데는 적당하지 않을 수도 있다. 비교적 드물지만, 그와 같은 경우에도 이 분야의 전문가라면 상술한 제조방법중 다른 방법을 사용하여 바라는 생성물을 합성할 수 있다. 생성된 화합물을 재침전 및/또는 재결정으로 정제할 수 있다. 이들은 적당한 용매내에서 결정성(알카리금속)염으로 부터 유리시켜 정제할 수도 있다.Depending on the nature of the starting materials, some of the methods described above may be low in yield of the desired benzenesulfonyl urea or may not be suitable for synthesizing the present compounds. Relatively rarely, even in such a case, a person skilled in the art can synthesize a desired product by using any of the above-described manufacturing methods. The resulting compound can be purified by reprecipitation and / or recrystallization. They can also be purified by liberation from crystalline (alkali metal) salts in a suitable solvent.

본 발명 화합물은 약학적으로 매우 유효한 활성, 즉 혈당 강하작용을 가지고 있다. 그러므로 본 화합물은 약제, 특히 당뇨병 치료제로 사용하는 것이 바람직하다. 상술한 벤젠 설포닐우레아의 혈당 강하 작용을 측정하기 위해 통상의 사료를 주는 토끼에게 본화합물을 유리화합물 또는 나트륨염 형태로 공급하고 공지방법(Hagedorn-Jensen의 방법) 또는 자동분석기를 사용하여 장시간 동안 혈당치를 측정한다.The compound of the present invention has a very effective pharmacological activity, that is, hypoglycemic activity. Therefore, the present compound is preferably used as a medicament, in particular for treating diabetes. In order to measure the hypoglycemic action of benzene sulfonylurea described above, the rabbit is fed with the feed in the form of a free compound or sodium salt to a rabbit that is fed with a conventional feed, and is used for a long time using a known method (Hagedorn-Jensen's method) or an automatic analyzer. Measure blood glucose levels.

혈당 강하 작용을 기지의 방법으로 시험 동물 체중 1kg당 활성물질 10, 2 또는 0.4mg의 용량을 사용하여, 정규 방법으로 측정한다.The hypoglycemic action is measured by the known method, using a dose of 10, 2 or 0.4 mg of active substance per kg of body weight of the test animal.

하기 화합물 I 내지 Ⅲ을 토끼에 2mg/kg의 용량으로 경구 투여하고 혈당치를 자동분석기로 장시간 동안 측정한다. 혈당치의 저하를 %로 표시하였다.The following compounds I to III are orally administered to rabbits at a dose of 2 mg / kg and blood glucose levels are measured for an extended period with an automatic analyzer. The decrease in blood glucose level was expressed in%.

I. N-(4-[2-(3-에틸-4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실 우레아.I. N- (4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexyl urea .

Ⅱ. N-(4-[2-(3-에틸-4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-메틸사이클로 헥실우레아.II. N- (4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-methylcyclo hexylurea.

Ⅲ. N-(4-[2-(3,4-디메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-메틸 사이클로헥실 우레아.III. N- (4- [2- (3,4-dimethyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-methyl cyclohexyl urea.

[표][table]

Figure kpo00004
Figure kpo00004

본 발명에 따른 아실 우레이도-알킬벤젠 설포닐 우레아는 강력한 혈당 강하 작용을 나타낸다. 또한, 본화합물은 독성을 나타내지 않는다. 본 화합물의 특성은 증가된 혈당량에 대한 췌장의 감소된 반응도를 단지 재정상화하는 그러한 낮은 용량으로 당뇨병을 치료할 수 있다는 점이다.Acyl ureido-alkylbenzene sulfonyl urea according to the present invention exhibits a strong hypoglycemic action. In addition, the compound does not exhibit toxicity. The property of the compound is that it can treat diabetes at such low doses that only renormalizes the pancreas's responsiveness to increased blood glucose.

우레이도 알킬기가 함유되어 었는 벤젠설포닐 우레아는 이미 수차례에 걸쳐서 기술된 바있다(독일연방 공화국 공개공보 제 1,670,700호, 독일연방공화국 특허 1,443,911호, 1,618,389호, 2,238,870호 참조). 그러나 본 발명 화합물이 상술한 바와 같은 현저한 특성을 나타낸다고 예측되지 못했다.Benzenesulfonyl urea, which contained ureido alkyl groups, has already been described several times (see Federal Republic of Germany Publication No. 1,670,700, Federal Republic of Germany Patent Nos. 1,443,911, 1,618,389, 2,238,870). However, it was not predicted that the compounds of the present invention exhibited the salient properties as described above.

본 발명의 설포닐 우레아는 당뇨병 치료를 위하여 경구 투여할 수 있는 제제를 제조하는데 사용하는 것이 바람직하다. 상기 화합물을 그대로 투여하거나 그들의 염형태 또는 염생성을 촉진시켜 주는 물질의 존재하에 투여할 수 있다. 염을 생성시키기 위해 알카리제(예를들면 알카리금속 수산화물, 탄산염 또는 중탄산염 또는 알카리토금속 수산화물, 탄산염 또는 중탄산염)를 사용할 수 있다. 설포닐 우레아 또는 그의 염 이외에도, 제제에는 다른 활성화합물을 함유시킬 수도 있다.The sulfonyl urea of the present invention is preferably used to prepare an orally administrable preparation for the treatment of diabetes. The compounds may be administered as such or in the presence of substances that promote their salt form or salt formation. Alkaline agents (eg, alkali metal hydroxides, carbonates or bicarbonates or alkali earth metal hydroxides, carbonates or bicarbonates) can be used to produce the salts. In addition to sulfonyl urea or salts thereof, the preparation may contain other active compounds.

적당한 치료제제로는 설포닐 우레아 또는 그의염 이외에도 통상 사용하는 담체 및 보조제(예를들면 탈크, 전분, 유당 또는 스테아르산 마그네슘)를 함유하는 정제가 바람직하다. 마쇄 또는 미세하게 분산된 형태의 활성화합물 또는 2가지 형태의 혼합물 형태의 활성화합물을 사용하는 것이 유리할 것이다.Suitable therapeutic agents are preferably tablets containing carriers and auxiliaries (eg talc, starch, lactose or magnesium stearate) which are commonly used in addition to sulfonyl urea or salts thereof. It would be advantageous to use active compounds in the form of ground or finely dispersed forms or mixtures of the two forms.

상술한 벤젠 설포닐 우레아를 제제중에 활성물질로서 함유하는 정제 또는 산제등의 제제는 적당한 용량형태로 만드는 것이 바람직하다. 사용하는 벤젠설포닐 우레아의 활성도와 바라는 효과를 조합시켜 복용량을 선택한다. 단위당 0.5내지 50mg, 바람직하게는 1내지 20mg이 적당하며, 복용 단위는 상기량을 초과하거나 그 이하일 수 있으며, 필요시 분할투여하거나 배가하여 사용할 수도 있다.Formulations such as tablets or powders containing the above-mentioned benzene sulfonyl urea as an active substance in the formulation are preferably made in a suitable dosage form. The dosage is selected by combining the desired effect with the activity of the benzenesulfonyl urea used. 0.5 to 50 mg, preferably 1 to 20 mg, per unit is suitable, and the dosage unit may be above or below the above amount, and may be divided or doubled as necessary.

하기 실시예는 본 발명의 설포닐 우레아의 합성에 사용할 수 있는 제조방법을 보여준다. 그러나, 하기 실시예로 본 발명을 제한하는 것은 아니다.The following examples show preparation methods that can be used for the synthesis of the sulfonyl urea of the present invention. However, the following examples do not limit the invention.

[실시예 1]Example 1

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸)]-벤젠설포닐)-N'-부틸우레아N- (4- [2- (4-Methyl-2-oxo-piperidine-1-carboxamido) -ethyl)]-benzenesulfonyl) -N'-butylurea

조생성물로 융점이 113내지 115℃인 4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설핀산(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포클로라이드와 아황산나트륨을 반응시켜 제조) 0.6g과 N-하이드록시-N'-부틸우레아 0.3g을 디옥산 50㎖에 용해시킨다. 디옥산 10㎖중의 티오닐 클로라이드 0.4g을 이 용액에 적가하고, 뱃취를 60℃로 2시간 가열한다. 이어서, 용매를 감압하여 증발시키고 물을 잔사에 적가하고 오일상의 물질을 불리하고 암모니아로 재침전시키면 융점이 155 내지 157℃인 표제화합물이 수득된다.As a crude product, 4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfinic acid (4- [2- (4) having a melting point of 113 to 115 ° C. -Methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfochloride and sodium sulfite) 0.6 g and N-hydroxy-N'-butylurea Dissolve in 50 ml of oxane. 0.4 g of thionyl chloride in 10 ml of dioxane is added dropwise to this solution, and the batch is heated to 60 ° C. for 2 hours. Subsequently, the solvent is evaporated under reduced pressure, water is added dropwise to the residue and the oily material is disadvantageous and reprecipitated with ammonia to give the title compound having a melting point of 155 to 157 ° C.

유사한 방법으로 하기 화합물을 수득한다. N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠-설포닐)-N'-4-메틸-사이클로헥실우레아, 융점 180내지 182℃(수성 에탄올로 부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미드-)-에틸]벤젠-설포닐)-N'-부틸 우레아, 융점 156내지 158℃(아세톤/물로 부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N°-사이클로펜틸 우레아, 융점 167내지 169℃(수성 메탄올로 부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸]벤젠-설포닐)-N'-이소부틸우레아, 융점 179내지 181℃(아세톤/물로부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N'-사이클로옥틸 우레아, 융점 170내지 172℃(아세톤/물로 부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠 설포닐-N'-사이클로헥실 우레아, 융점 197내지 199℃, N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠 설포닐-N'-3,4-디메틸사이클로헥실우레아, 융점 139내지 141℃(아세톤/물로부터), N-(4-[2-(2-옥소피페리딘-1-카복스아미도)-에틸]-벤젠-설포닐)-N'-메틸-사이클로펜틸-메틸우레아, 융점 172내지 174℃(아세톤/물로 부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N'-노르트리데실 우레아, 융점179내지 181℃(아세톤/물로부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N'-비사이클로 [2.2.1]헵트-5-엔-2-일-메틸 우레아, 융점 184내지 186℃(아세톤/물로 부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N'-헥실 우레아, 융점 142내지 144℃(아세톤/물로부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N'-3-메틸-사이클로펜틸우레아, 융점 166내지 168℃(아세톤/물로부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N'-사이클로헥스-3-에닐-메틸 우레아(X 1/2H2O) 융점 136내지 138℃(아세톤/물로부터), N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠-설포닐)-N'-4-이소프로필-사이클로헥실 우레아, 융점 158내지 160℃(아세톤/물로부터), N-(4-[2-(2-옥소-헥부메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실우레아, 융점 179내지 181℃(에탄올로부터), N-(4-[2-(2-옥소-헥사메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸-사이클로헥실우레아, 융점 181내지 182℃(아세톤/물로부터), N-(4-[2-(2-옥소-헥사메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-부틸우레아, 융점 117내지 119℃(에탄올로부터), N-(4-[2-(2-옥소-헥부메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-에틸-사이클로헥실 우레아, 융점 162내지 164℃(묽은 아세톤으로 부터), N-(4-[2-(2-옥소-헥사메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-3-메틸-사이클로펜틸우레아, 융점 161내지 163℃(묽은 아세톤으로부터), N-(4-[2-(2-옥소-헥사메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로펜틸우레아, 융점 148내지 150℃(아세톤＼물로부터), N-(4-[2-(2-옥소-헥사메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-헥실우레아, 융점 142내지 144℃(아세톤/물로부터), N-(4-[2-(2-옥소-헥사메틸렌-이민-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-이소프로필-사이클로헥실우레아, 융점 173내지 175℃(묽은 아세톤으로부터), N-(4-[2-(1-옥소-1,2,3,4,5,6,7,8-옥타하이드로-이소퀴놀린-2-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실우레아 융점 176내지 177℃, N-(4-[2-(1-옥소-1,2,3,4,5,6,7,8-옥타하이드로-이소퀴놀린-2-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸-사이클로헥실우레아,융점 180내지 182℃(에탄올로부터), N-(4-[2-(1-옥소-헥사하이드로-이소-인돌린-2-카복스 아미도)-에틸] 벤젠설포닐)-N'-사이클로헥실우렌아, 융점 139내지 140℃, N-(4-[2-(1-옥소-헥사하이드로-이소-인돌린-2-카복스 아미도)-에틸]-벤젠설포닐)-N'-(4-메틸-사이클로헥실) 우레아, 융점 153내지 155℃(에탄올로부터), N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸사이클로헥실우레아, 융점 190내지 191℃(묽은 아세톤으로부터), N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실우레아, 융점 177내지 178℃, N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-에틸사이클로헥실우레아, 융점 178내지 180℃(묽은 에탄올로부터), N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸사이클로헥실-3-에틸우레아, 융점173내지175℃(묽은 아세톤으로부터),In a similar manner the following compounds are obtained. N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] -benzene-sulfonyl) -N'-4-methyl-cyclohexylurea, melting point 180-182 degreeC (From aqueous ethanol), N- (4- [2- (2-oxo-piperidine-1-carboxamide-)-ethyl] benzene-sulfonyl) -N'-butyl urea, melting point 156-158 ° C (from acetone / water), N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] benzene-sulfonyl) -N ° -cyclopentyl urea, melting point 167 To 169 ° C. (from aqueous methanol), N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] benzene-sulfonyl) -N'-isobutylurea, Melting point 179 to 181 ° C. (from acetone / water), N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] benzene-sulfonyl) -N'-cyclooctyl Urea, melting point 170-172 ° C. (from acetone / water), N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] -benzene sulfonyl-N'-cyclo Hexyl urea, melting point 197-199 ° C., N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] Benzene sulfonyl-N'-3,4-dimethylcyclohexylurea, melting point 139-141 ° C. (from acetone / water), N- (4- [2- (2-oxopiperidine-1-carboxamido ) -Ethyl] -benzene-sulfonyl) -N'-methyl-cyclopentyl-methylurea, melting point 172-174 ° C (from acetone / water), N- (4- [2- (2-oxo-piperidine -1-carboxamido) -ethyl] benzene-sulfonyl) -N'-nortridecyl urea, melting point 179-181 ° C. (from acetone / water), N- (4- [2- (2-oxo-) Piperidine-1-carboxamido) -ethyl] benzene-sulfonyl) -N'-bicyclo [2.2.1] hept-5-en-2-yl-methyl urea, melting point 184-186 ° C. (acetone From water), N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] benzene-sulfonyl) -N'-hexyl urea, melting point 142-144 ° C. ( Acetone / water), N- (4- [2- (2-oxo-piperidine-1-carboxamido) -ethyl] benzene-sulfonyl) -N'-3-methyl-cyclopentylurea, Melting point 166-168 DEG C (from acetone / water), N- (4- [2- (2-oxo-piperidine-1-carbox Not shown) -ethyl] benzene-sulfonyl) -N'- cyclo hex-3-enyl-methyl-urea (X 1 / 2H 2 O) melting point from 136 to 138 ℃ (acetone / water), N- (4- [2 -(2-oxo-piperidine-1-carboxamido) -ethyl] benzene-sulfonyl) -N'-4-isopropyl-cyclohexyl urea, melting point 158-160 ° C. (from acetone / water), N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 179-181 ° C (from ethanol) , N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-methyl-cyclohexylurea, melting point 181 to 182 ° C (from acetone / water), N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-butylurea, melting point 117 To 119 ° C. (from ethanol), N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-ethyl-cyclo Hexyl urea, melting point 162-164 ° C (pour with diluted acetone ), N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-3-methyl-cyclopentylurea, melting point 161 to 163 ° C. (from dilute acetone), N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclopentylurea, melting point 148-150 ° C. (from acetone water), N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4- Hexylurea, melting point 142-144 DEG C (from acetone / water), N- (4- [2- (2-oxo-hexamethylene-imine-1-carboxamido) -ethyl] -benzenesulfonyl) -N '-4-isopropyl-cyclohexylurea, melting point 173-175 ° C. (from dilute acetone), N- (4- [2- (1-oxo-1,2,3,4,5,6,7,8 -Octahydro-isoquinoline-2-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea melting point 176-177 DEG C, N- (4- [2- (1-oxo-1, 2,3,4,5,6,7,8-octahydro-isoquinoline-2-carboxamido) -ethyl] -benzenesulfonyl)- N'-4-methyl-cyclohexylurea, melting point 180-182 캜 (from ethanol), N- (4- [2- (1-oxo-hexahydro-iso-indolin-2-carbox amido)- Ethyl] benzenesulfonyl) -N'-cyclohexylurea, melting point 139-140 degreeC, N- (4- [2- (1-oxo-hexahydro-iso-indolin-2-carbox amido)- Ethyl] -benzenesulfonyl) -N '-(4-methyl-cyclohexyl) urea, melting point 153-155 DEG C (from ethanol), N- (4- [2- (4-methyl-2-oxo-piperi) Din-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-methylcyclohexylurea, melting point 190 to 191 ° C (from dilute acetone), N- (4- [2- (4- Methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 177-178 degreeC, N- (4- [2- (4- Methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-ethylcyclohexylurea, melting point 178-180 ° C (from dilute ethanol), N- ( 4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido ) -Ethyl] -benzenesulfonyl) -N'-4-methylcyclohexyl-3-ethylurea, melting point 173-175 캜 (from dilute acetone),

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도) -에틸]-벤젠설포닐) -N' -4- 사이클로펜틸우레아, 융점 177내지 179℃(묽은 메탄올로 부터),N- (4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-cyclopentylurea, melting point 177-179 ℃ (from dilute methanol),

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐) -N' -4- 이소프로필사이클로헥실우레아, 융점 171내지 173℃(메탄올로 부터),N- (4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-isopropylcyclohexylurea, melting point 171 To 173 ° C. (from methanol),

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헵틸우레아, 융점 142내지 143℃(묽은 메탄올로 부터),N- (4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cycloheptylurea, melting point 142-143 degreeC ( From dilute methanol),

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-3-메틸사이클로펜틸우레아, 융점 145내지 147℃(묽은 아세톤으로부터),N- (4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-3-methylcyclopentylurea, melting point 145- 147 ° C. (from dilute acetone),

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠설포닐)-N'-비사이클로[2.2.1]-헵트-5-엔-2-일-메틸우레아, 융점 164내지 166℃(묽은 아세톤으로부터),N- (4- [2- (4-Methyl-2-oxo-piperidine-1-carboxamido) -ethyl] benzenesulfonyl) -N'-bicyclo [2.2.1] -hept-5 -En-2-yl-methylurea, melting point 164-166 캜 (from dilute acetone),

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠설포닐)-N'-3-메틸사이클로펜틸메틸우레아, 융점 152내지 154℃(묽은 아세톤으로 부터),N- (4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] benzenesulfonyl) -N'-3-methylcyclopentylmethylurea, melting point 152 to 154 ° C. (from dilute acetone),

N-(4-[2-(4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠설포닐)-N'-아다만틸우레아 융점, 176내지 178℃(묽은 아세톤으로 부터),N- (4- [2- (4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] benzenesulfonyl) -N'-adamantylurea melting point, 176-178 ° C ( From dilute acetone),

N-(4-[2-(3-부틸-4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실우레아, 융점 123내지 125℃(메탄올로 부터),N- (4- [2- (3-butyl-4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 123 To 125 ° C. (from methanol),

N-(4-[2-(3-부틸-4-메틸-2-옥소-피페리딘-1-카복스아미도)-에틸] 벤젠설포닐)-N'-4-메틸-사이클로헥실우레아, 융점 131내 지 133℃(메탄올로 부터),N- (4- [2- (3-butyl-4-methyl-2-oxo-piperidine-1-carboxamido) -ethyl] benzenesulfonyl) -N'-4-methyl-cyclohexylurea Melting point from 131 to 133 ° C (from methanol),

N-(4-[2-옥소-피롤리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실우레아, 융점 189내지190℃,N- (4- [2-oxo-pyrrolidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 189-190 degreeC,

N-(4-[2-(2-옥소-피롤리딘-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸-사이클로헥실우레아, 융점 179내지 181℃(묽은 에탄올로 부터),N- (4- [2- (2-oxo-pyrrolidine-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-methyl-cyclohexylurea, melting point 179-181 degreeC ( From dilute ethanol),

N-(4-[2-(3,4-디메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실우레아, 융점 200내지 202℃(메탄올/디옥산으로 부디),N- (4- [2- (3,4-dimethyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 200 to 202 degrees Celsius (please come with methanol / dioxane),

N-(4-[2-(3,4-디메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸-사이클로헥실우레아, 융점 208내지 210℃(묽은 메탄올로 부터),N- (4- [2- (3,4-dimethyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-methyl-cyclohexylurea Melting point 208-210 ° C. (from dilute methanol),

N-(4-[2-(3,4-디메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-부틸우레아, 융점 198내지 200℃(메탄올/디옥산으로 부터),N- (4- [2- (3,4-dimethyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-butylurea, melting point 198-200 ° C (from methanol / dioxane),

N-(4-[2-(4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실우레아, 융점 195내지 197℃(묽은 메탄올/디옥산으로 부터),N- (4- [2- (4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 195-197 degreeC (From dilute methanol / dioxane),

N-(4-[2-(4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸-사이클로헥실우레아, 융점 199내지 201℃(묽은 디옥산으로 부터),N- (4- [2- (4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-methyl-cyclohexylurea, melting point 199 to 201 ° C (from dilute dioxane),

N-(4-[2-(4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-부틸우레아, 융점 189내지 191℃(묽은 메탄올/디옥산으로 부터),N- (4- [2- (4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-butylurea, melting point 189-191 degreeC ( From dilute methanol / dioxane),

N-(4-[2-(2-옥소-피페리딘-1-카복스아미도)-프로필]-벤젠설포닐)-N'-사이클로헥실우레아, 융점 176내지 177℃N- (4- [2- (2-oxo-piperidine-1-carboxamido) -propyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 176-177 degreeC

N-(4-[2-(3-에틸-4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-사이클로헥실 우레아, 융점 185내지 187℃(묽은 아세톤으로 부터),N- (4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexyl urea, melting point 185 to 187 ° C (from dilute acetone),

N-(4-[2-(3-에틸-4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐)-N'-4-메틸-사이클로헥실우레아, 융점 168내지 170℃(묽은 아세톤으로 부터),N- (4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-methyl-cyclo Hexylurea, melting point 168-170 ° C (from dilute acetone),

N-(4-[2-(3-에틸-4-메틸-2-옥소-3-피롤린-1-카복스 아미도)-에틸]-벤젠설포닐) -N'-부틸우레아, 융점 151내지 153℃(메탄올로 부터),N- (4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carbox amido) -ethyl] -benzenesulfonyl) -N'-butylurea, melting point 151 To 153 ° C. (from methanol),

N-(4-[2-(3-부틸-4-베틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐) -N'-사이클로헥실우레아, 융점 173내지 175℃,N- (4- [2- (3-butyl-4-betayl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-cyclohexylurea, melting point 173-175 캜,

N-(4-[2-(3-부틸-4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐) -N'-4-메틸-사이클로헥실우레아, 융점 178내지 180℃(묽은 메탄올로 부터),N- (4- [2- (3-butyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-methyl-cyclo Hexylurea, melting point 178-180 ° C (from dilute methanol),

N-(4-[2-(3-부틸-4-메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]벤젠설포닐)-N1-부틸 우레아, 융점 127내지 129℃(묽은 메탄올로 부터),N- (4- [2- (3-butyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] benzenesulfonyl) -N 1 -butyl urea, melting point 127 to 129 ° C. (from dilute methanol),

N -(4-[2-(3,4-디메틸-2-옥소-3-피롤린-1-카복스아미도)-에틸]-벤젠설포닐) -N' -4-에틸-사이클로헥실우레아, 융점 203내지 205℃(메탄올/디옥산으로 부터).N- (4- [2- (3,4-dimethyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl) -N'-4-ethyl-cyclohexylurea Melting point 203-205 ° C. (from methanol / dioxane).

Claims (1)

일반식(1)의 벤젠설핀산의 할라이드 또는, 산 축합제의 존재하에, 일반식(1)의 벤젠설핀산 또는 그의 알칼리금속염을 N-R1-N'-하이드록시우레아와 반응시킴을 특징으로 하여 일반식(I)의 설포닐 우레아 또는 그의 생리학적으로 무독한 염을 제조하는 방법.In the presence of a halide of benzenesulfinic acid of the general formula (1) or an acid condensing agent, the benzenesulfinic acid or its alkali metal salt of the general formula (1) is reacted with NR 1 -N'-hydroxyurea, characterized by A process for preparing sulfonyl urea of formula (I) or a physiologically toxic salt thereof.
Figure kpo00005
Figure kpo00005
 상기식에서In the above formula X는 각각 탄소수 1내지 4의 알킬그룹 3개 까지로 임의 치환된 탄소수 3내지 6의 알킬렌 또는X is alkylene of 3 to 6 carbon atoms optionally substituted with up to 3 alkyl groups of 1 to 4 carbon atoms, or 알케닐렌이거나,
Figure kpo00006
그룹이 구조식Alkenylene,
Figure kpo00006
Group structural formula
Figure kpo00007
Figure kpo00007
 비사이클 시스템이며,Is a bicycle system, Y는 탄소수 2내지 3의 알킬렌이고Y is alkylene having 2 to 3 carbon atoms R1은 탄소수 4내지 6의 알킬, 사이클로알킬, 알킬사이클로알킬, 디알킬사이클로알킬, 사이클로알킬알킬, 탄소수 4내지 9의 사이클로알케닐 또는 알킬사이클로알케닐, 메틸 사이클로펜틸메틸, 사이클로헥세닐 메틸, 클로로사이클로헥실, 메톡시 사이클로헥실, 비사이클로헵틸, 비사이클로헵테닐, 비사이클로헵틸메틸, 비사이클로헵테닐메틸, 비사이클로옥틸, 노르트리사이크릴, 아다맨틸 또는 벤질이다.R 1 is alkyl having 4 to 6 carbon atoms, cycloalkyl, alkylcycloalkyl, dialkylcycloalkyl, cycloalkylalkyl, cycloalkenyl or alkylcycloalkenyl having 4 to 9 carbon atoms, methyl cyclopentylmethyl, cyclohexenyl methyl, Chlorocyclohexyl, methoxy cyclohexyl, bicycloheptyl, bicycloheptenyl, bicycloheptylmethyl, bicycloheptenylmethyl, bicyclooctyl, nortricyclyl, adamantyl or benzyl.
KR1019840005313A 1980-12-23 1984-08-30 Process for preparing sulfonylureas KR840002087B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019840005313A KR840002087B1 (en) 1980-12-23 1984-08-30 Process for preparing sulfonylureas

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1019800004902A KR840001969B1 (en) 1980-12-23 1980-12-23 Process for preparing sulfonglureas
KR1019840005313A KR840002087B1 (en) 1980-12-23 1984-08-30 Process for preparing sulfonylureas

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
KR1019800004902A Division KR840001969B1 (en) 1980-12-23 1980-12-23 Process for preparing sulfonglureas

Publications (1)

Publication Number Publication Date
KR840002087B1 true KR840002087B1 (en) 1984-11-14

Family

ID=19218621

Family Applications (5)

Application Number Title Priority Date Filing Date
KR1019800004902A KR840001969B1 (en) 1980-12-23 1980-12-23 Process for preparing sulfonglureas
KR1019840005312A KR840001971B1 (en) 1980-12-23 1984-08-30 Process for preparing sulfonglureas
KR1019840005313A KR840002087B1 (en) 1980-12-23 1984-08-30 Process for preparing sulfonylureas
KR1019840005310A KR840001984B1 (en) 1980-12-23 1984-08-30 Process for preparing snlfonylureas
KR1019840005311A KR840001970B1 (en) 1980-12-23 1984-08-30 Process for preparing sulfonylureas

Family Applications Before (2)

Application Number Title Priority Date Filing Date
KR1019800004902A KR840001969B1 (en) 1980-12-23 1980-12-23 Process for preparing sulfonglureas
KR1019840005312A KR840001971B1 (en) 1980-12-23 1984-08-30 Process for preparing sulfonglureas

Family Applications After (2)

Application Number Title Priority Date Filing Date
KR1019840005310A KR840001984B1 (en) 1980-12-23 1984-08-30 Process for preparing snlfonylureas
KR1019840005311A KR840001970B1 (en) 1980-12-23 1984-08-30 Process for preparing sulfonylureas

Country Status (1)

Country Link
KR (5) KR840001969B1 (en)

Also Published As

Publication number Publication date
KR830004241A (en) 1983-07-09
KR840001969B1 (en) 1984-10-26
KR840001971B1 (en) 1984-10-26
KR840001970B1 (en) 1984-10-26
KR840001984B1 (en) 1984-10-26

Similar Documents

Publication Publication Date Title
EP0196222B1 (en) Hypoglycemic agent
US4379785A (en) Heterocyclic substituted sulfonyl ureas, and their use
EP0014951A2 (en) Heterocyclic oxypropanolamine derivatives, process for their preparation and medicines containing these compounds
EP0053407B1 (en) New imidazolylphenyl amidines, processes for their preparation and their pharmaceutical use, and intermediates of preparation
US3639477A (en) Novel propoxyguanidine compounds and means of producing the same
DE3017684C2 (en)
FR2595695A1 (en) N - ((((2-HYDROXYHYL) PHENYL) (PHENYL) METHYLENE) AMINO-2) ETHYL) ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
US4395413A (en) Oxime ethers and pharmaceutical compositions containing the same
KR800000944B1 (en) Benzenesulfonyl-ureas and process for preparing them
KR840002087B1 (en) Process for preparing sulfonylureas
US4285943A (en) Novel pharmaceutical compositions incorporating an aryltrifluoroethanol
US4409240A (en) Derivatives of dihydroxybenzoic acid and pharmaceutical composition thereof
KR880002706B1 (en) Sulfonyl urea preparation process
US4029666A (en) Benzenesulfonyl-ureas and process for preparing them
US3845123A (en) Phenoxypropanolamine therapeutic agents
US3072720A (en) Novel n-arylsulfonyl-n'-(2, 5-endomethylene-1, 2, 5, 6-tetrahydrobenzyl) ureas
US4123531A (en) Anti-convulsant N-ethanolamine diphenyl acetamides
HU195644B (en) Process for producing new phenyl-acetonitril derivatives and pharmaceutical compositions containing them as active components
US3789068A (en) Aminoethanesulfonic acid derivative
SE434835B (en) N- (1-METHYL-2-PYRROLIDINYLMETHYL) -2,3-DIMETOXY-5-METHYLSULPHAMOYL-BENZAMIDE, ITS PREPARATION AND PHARMACOLOGICAL COMPOSITION CONTAINING THIS NEW BENZAMIDE
US3928341A (en) N-Aminoalkyl-4-anilino pyridines
CA1106389A (en) 2-(phenylalkylhydrazono)-propionic acid derivatives and the preparation thereof
US3914426A (en) Piperidinesulfonylurea derivatives for lowering blood sugar levels
US3259544A (en) Antidiabetic composition and method
US3562258A (en) (**1-(p-amino benzene sulfonyl)-n**3-(4,5-dimethyl oxazolyl-(2)) guanidine

Legal Events

Date Code Title Description
A107 Divisional application of patent
G160 Decision to publish patent application
E701 Decision to grant or registration of patent right
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 19941101

Year of fee payment: 11

LAPS Lapse due to unpaid annual fee