KR840001072B1 - Process for the preparation amide of p-isobuthy phenyl propionic acid - Google Patents
Process for the preparation amide of p-isobuthy phenyl propionic acid Download PDFInfo
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- KR840001072B1 KR840001072B1 KR1019810002639A KR810002639A KR840001072B1 KR 840001072 B1 KR840001072 B1 KR 840001072B1 KR 1019810002639 A KR1019810002639 A KR 1019810002639A KR 810002639 A KR810002639 A KR 810002639A KR 840001072 B1 KR840001072 B1 KR 840001072B1
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Abstract
Description
본 발명은 하기 일반식의 p-이소부틸-페닐-프로피온산의 마미드 유도체의 제조방법에 관한 것이다.The present invention relates to a method for producing a mamid derivative of p-isobutyl-phenyl-propionic acid of the following general formula.
식중, X는 리신, 메타트리플루오로톨루이딘, 글루타민산 및 아스파라긴산 중에서 선택된 치환 아민기를 나타낸다.Wherein X represents a substituted amine group selected from lysine, metatrifluorotoluidine, glutamic acid and aspartic acid.
p-이소부틸-페닐-프로피온산의 소염 특성은 공지되어 있다.The anti-inflammatory properties of p-isobutyl-phenyl-propionic acid are known.
또한 염증치료에 사용되는 대부분의 약제와 같이, 이 산은 예를 들어 장기간 치료하는데에 중요한 요인들로서, 예를 들면 위장내에서의 내약력(耐藥力)이 낮고, 무시할 수 없는 독성이 있는등 좋지못한 부작용을 나타내는 것으로 알려졌다.Also, like most drugs used to treat inflammation, this acid is an important factor, for example, for long-term treatment, such as poor tolerability in the stomach and insignificant toxicity. It has been known to indicate adverse side effects.
그러나, 본 발명자는 본 발명의 아미드 유도체가 p-이소부틸-페닐-프로피온산에 의해서 전형적으로 나타나는 소염작용 이외에 독성이 적고 위장내에서의 내약력이 큰 사실을 발견했다.However, the present inventors have found that the amide derivative of the present invention is less toxic and has greater tolerability in the stomach in addition to the anti-inflammatory action that is typical of p-isobutyl-phenyl-propionic acid.
상기 일반식(I)의 아미드 유도체를 제조하기 위한 본 발명의 제조공정은 다음과 같다.The production process of the present invention for preparing the amide derivative of the general formula (I) is as follows.
a) p-이소부틸-페닐-프로피온산을 과량의 염소화제(예 : 염화티오닐 또는 오염화인이 적합함)로 가온 염소화처리를 행하고,a) warming the p-isobutyl-phenyl-propionic acid with an excess of chlorinating agent (e.g., thionyl chloride or phosphorus pentachloride),
b) D-이소부틸-페닐-로피온산의 염화물을 알칼리수 및 피리딘 중에서 선택된 반응매질 중에서 아민 유도체와 저온에서 반응시킨다.b) The chloride of D-isobutyl-phenyl-lopionic acid is reacted at low temperature with an amine derivative in a reaction medium selected from alkaline water and pyridine.
또한 약리학적으로 허용되는 유기 또는 무기염기에 의해서 생성되는 아미드의 유리산 반응기의 염화반응으로 한 단게 더 반응이 진행될 수 있다는 것을 예견할 수 있다.It can also be foreseen that the reaction can proceed further by the chlorination of the free acid reactor of the amide produced by the pharmacologically acceptable organic or inorganic base.
본 발명의 실시예를 들면 다음과 같다.Examples of the present invention are as follows.
[실시예 1]Example 1
a) p-이소부틸-페닐-프로피온산의 염화물a) chlorides of p-isobutyl-phenyl-propionic acid
염화티오닐 120ml를 p-이소부틸-페닐-프로피온산 50g에 가하고, 이 혼합물을 75℃까지 점차적으로 가열했다. 반응상태를 조절하기 위하여, 반응혼합물로부터 가스의 발생을 가스트랩(gas trap)에 의해서 이가스의 발생이 멈출때까지 감시하고, 이 가스의 발생이 멈출때 이 반응의 종기를 알아냈다. 과량의 염화티오닐은 증류하여 제거하고, 이어서 p-이소부틸-페닐-프로피온산의 염화물은 진공증류하여 회수하였다.120 ml of thionyl chloride was added to 50 g of p-isobutyl-phenyl-propionic acid, and the mixture was gradually heated to 75 ° C. In order to control the reaction state, the generation of gas from the reaction mixture was monitored by the gas trap until the generation of this gas stopped, and the end of this reaction was found when the generation of this gas stopped. Excess thionyl chloride was distilled off and then the chloride of p-isobutyl-phenyl-propionic acid was recovered by vacuum distillation.
b) p-이소부틸-페닐-프로피온산의 글루타민산아미드b) Glutamic acid amide of p-isobutyl-phenyl-propionic acid
물 20ml에 용해시킨 글루타민산 14.7g의 용액을 물 20ml에 용해시킨 고상 NaOH 8g의 용액에 가했다.A solution of 14.7 g of glutamic acid dissolved in 20 ml of water was added to a solution of 8 g of solid NaOH dissolved in 20 ml of water.
이 혼합물을 얼음(2입방)을 가해서 냉각시키고, 교반하에 p-이소부틸-페닐-프로피온산의 염화물을 여기에 적가했다. 온도는 약 0℃로 유지시키고, 이 혼합물을 수시간후에 pH가 산성을 나타낼때까지, 교반하에 유지시켰다. 수산나트륨(수용액중 1.6g)을 첨가하고 이 혼합물을 2일동안 방치해 두었다.The mixture was cooled by adding ice (2 cubic), and the chloride of p-isobutyl-phenyl-propionic acid was added dropwise thereto under stirring. The temperature was maintained at about 0 ° C. and the mixture was kept under stirring until after several hours the pH showed acidic. Sodium hydroxide (1.6 g in aqueous solution) was added and the mixture was left for 2 days.
묽은 염산으로 산성화하여, 백색점질의 생성물을 침전시키고, 시클로헥산을 가한뒤 완전히 혼합하였다.Acidified with diluted hydrochloric acid, the white viscous product was precipitated, cyclohexane was added and mixed thoroughly.
이와 같이 하여 물, 묽은 염산 및 시클로헥산에 불용성인 생성물 29g을 얻었다.This gave 29 g of a product insoluble in water, dilute hydrochloric acid and cyclohexane.
이와 같이 얻은 생성물의 그 나트륨염을 에타놀-아세톤 중에서 NaOH 수용액으로 얻었다.The sodium salt of the product thus obtained was obtained as an aqueous NaOH solution in ethanol-acetone.
같은 방법에 의해서 아스파르긴산 및 리신의 아미드를 제조하며, 이때 반응하기 전에 구리착체(錯體)로서 리신의 착화물(錯化物)인 리신아미드에 관해서 주의할 필요가 있다.By the same method, amides of aspartic acid and lysine are prepared, and attention should be paid to lysineamide, which is a complex of lysine as a copper complex, before the reaction.
[실시예 2]Example 2
메타트리플루오로톨루이딘의 p-이소부틸-페닐-프로피온 아미드P-isobutyl-phenyl-propion amide of metatrifluorotoluidine
p-이소부틸-페닐-프로피온산의 염화물을 실시예 1에서와 같이 제조하고 이 염화물 27g을 클로로포름 500ml에 용해시키고, 이 용액에 피리딘 9.5ml을 부가했다.A chloride of p-isobutyl-phenyl-propionic acid was prepared as in Example 1, 27 g of this chloride was dissolved in 500 ml of chloroform, and 9.5 ml of pyridine was added to this solution.
이 용액을 교반하면서, 이 용액에 클로로포름 50ml 중에 용해시킨 메타트리플루오로톨루이딘 16.1g 용액을 부가했다. 이 반응은 발열반응이며, 반응온도는 60℃까지 자연적으로 상승하게 하고, 그후 반응혼합물의 온도를 실온까지 자연적으로 냉각시켜 하룻밤 동안 방치했다.While stirring this solution, the solution of 16.1 g of metatrifluorotoluidine dissolved in 50 ml of chloroform was added. This reaction was exothermic, and the reaction temperature naturally rose to 60 ° C., and then the temperature of the reaction mixture was naturally cooled to room temperature and left overnight.
이어서, 이 반응혼합물을 물로 완전히 세척하고, 클로로포름 추출물을 농축 건조시켜서 결정(結晶)으로 되는 유상물(油狀物)을 얻었다.Subsequently, the reaction mixture was washed thoroughly with water, and the chloroform extract was concentrated to dryness to obtain an oily substance that was crystallized.
결정화시킨 후에, 메타트리플루오로톨루이딘의 p-이소부틸-페닐-프로피온아미드 31g을 분말형태로 얻었는데, 이것은 물에 불용성이고, 대부분의 유기용매에 가용성이며, 융점은 84-86℃이였다.After crystallization, 31 g of p-isobutyl-phenyl-propionamide of metatrifluorotoluidine were obtained in powder form, which was insoluble in water, soluble in most organic solvents, and had a melting point of 84-86 ° C.
본 발명의 화합물을 약리학적으로 시험한 결과, 적당하거나 거의 무시할 정도의 독성을 나타내었다.Pharmacological testing of the compounds of the present invention showed moderate or almost negligible toxicity.
실제로 본 발명의 4가지 화합물들은 모두 새앙쥐에 경우 투여한 결과 900mg/kg 이상의 LD50치를 나타냈다.In fact, all four compounds of the present invention showed an LD 50 value of 900 mg / kg or more when administered to a rat.
이 화합물들의 소염작용은 카오린과 계란흰자에 의해서 발생되는 부종에 대한 고전적인 시험으로 시험하였으며, 이 시험방법은 염증의 발병과정이 상이한 두 가지 형태에 대해서 시험한 것이다. 쥐의 경골족근골의 연결부에 주사한 카오린은 만성염증을 일으키고, 쥐의 발바닥에 주사한 게란흰자는 급성 염증상태를 유발시켰다.The anti-inflammatory activity of these compounds was tested in the classical test for edema caused by kaolin and egg whites, which tested two different forms of inflammation. Caoline injected into the tibialis anterior junction of the rat caused chronic inflammation, while geran white injected into the rat's foot caused an acute inflammatory condition.
본 발명의 화합물들은 위장내에서의 내약력이 양호했다.The compounds of the present invention had good tolerability in the stomach.
본 발명의 화합물에 관하여 상기한 바와 같이 에비약리시험의 결과를 토대로 하여, 더욱 구체적인 약리 시험을 실시하였는데, 이 중에서, 약자로 BT-03으로 나타내는 메타트리플루오로톨루이딘의 p-이소부틸-페닐-프로피온아미드에 관한 시험결과를 다음에 기재했다.As described above with respect to the compound of the present invention, a more specific pharmacological test was conducted, among which p-isobutyl-phenyl- of metatrifluorotoluidine, abbreviated as BT-03, was used. The test results regarding propionamide are described below.
상기 화합물은 경구 및 복강내의 투약결과, 매우 낮은 금성독성을 나타내었다. 실제로 쥐에 4000mg/kg 정도 경구 투약하였지만, LD50치를 측정할 수 있었다.The compound showed very low venus toxicity as a result of oral and intraperitoneal administration. In fact, rats were orally dosed at 4000 mg / kg, but LD 50 levels could be measured.
새앙쥐에 있어서 경구투약은 허용되지 아니하므로 LD50치를 측정할 수 없으므로 복강내로 투약해서 측정한 결과, 동물의 수컷과 암컷에 있어서 LD50치는 각각 940mg/kg과 1190mg/kg이였다.Oral dosing was not acceptable in rats, so LD 50 levels could not be measured. As a result, the LD 50 values were 940 mg / kg and 1190 mg / kg in males and females, respectively.
쥐에 100mg/kg 이내의 투약량을 28일동안 반복하여 투약하였을때, 고려했던 만큼의 동물의 신체성장, 또는 혈액학적 및 혈액화학적 파라미터의 변화가 일어나지 않았다. 200mg/kg을 투약했을때 시험기간동안 두마리의 동물이 죽었다.When rats were dosed within 100 mg / kg repeatedly for 28 days, there was no change in body growth or hematological and hemochemical parameters of the animals as considered. Two animals died during the trial when 200 mg / kg was administered.
다음 표 1에 쥐의 급성독성 데이타를 유리산[보통명칭은 이부프로펜 (Ibu profen)으로 나타냄]과 비교하여 나타냈다.The acute toxicity data of rats are shown in Table 1 below compared to free acid (common name is ibuprofen).
[표 1] 쥐에 있어서 복강내의 경로로 주사한 BT-03 및 이부프로펜의 급성독성Table 1 Acute Toxicity of BT-03 and Ibuprofen Injected by Intraperitoneal Pathways in Rats
(주) : f.1=신뢰한계.Note: f.1 = confidence limit.
표 2에 쥐에 있어서 28일동안 시험한 BT-03의 아급성 독선(TD50)의 데이타를 대조용으로 이부프로펜과 나프록센(Naproxene)(즉, d-2(6'-메톡시-2'-나프틸)-프로피온산)의 TD50데이타와 비교해서 나타냈다.Table 2 shows ibuprofen and naproxene (ie, d-2 (6'-methoxy-2'-) as a control for the data of subacute virulence (TD 50 ) of BT-03 tested in rats for 28 days. It is shown in comparison with the data of the TD 50 acid) -naphthyl).
[표 2]TABLE 2
쥐의 암컷과 수컷의 전체 사망율Overall mortality rate in females and males
광범위한 치료용으로 소염작용을 갖는 물질로 알려진 나프록센과 비교해서, 후자의 물질은 독성이 더 강하며, 실제로 그 독성은 본 발명의 화합물보다 약 3.8배나 더 강하다.Compared to naproxen, which is known to have anti-inflammatory properties for a wide range of treatments, the latter is more toxic, and in fact its toxicity is about 3.8 times stronger than the compounds of the present invention.
새앙쥐와 토끼에 실시한 조사에서 아무런 배자기형 발생(胚子畸形發生)이나 또는 배아독성 작용을 나타나지 않았다.Investigations in birds and rabbits showed no embryonic malformations or embryotoxic effects.
약리시험에서 본 발명의 화합물은 명백한 소염작용과 진통작용을 나타내었다.In the pharmacological test, the compound of the present invention showed obvious anti-inflammatory and analgesic action.
다음 시험테타가 이를 확인해 주었다.The following test theta confirmed this.
(A) 쥐의 발에 카라게닌에 의해서 생기는 수종(水種)의 억제.(A) Inhibition of the species produced by carrageenan in the rat's foot.
(Coubon R. Carlier R., wandersmissen L. Arch. Int. Pharmacodyn. 99,474, 1954 참조).(See Coubon R. Carlier R., wandersmissen L. Arch. Int. Pharmacodyn. 99,474, 1954).
본 발명의 화합물의 소염작용을 대조동물에 발생한 수종을 참고로 하여 카라게닌에 의하여 발생한 수종의 억제백분율에 관하여, 소염작용이 양호한 것으로 알려진 화합물, 즉 이부프로펜과 나프록센과 비교해서 평가했다.The anti-inflammatory activity of the compounds of the present invention was evaluated with reference to the species which occurred in the control animals in comparison with the compounds known to have good anti-inflammatory action, ie, ibuprofen and naproxen, with respect to the percentage of inhibition caused by carrageenan.
이 수종은 쥐에서 발생하였으며, 대조동물에 있어서는 발이 57.55%나 부어올랐다.This species occurred in rats, with swelling of 57.55% in the control animals.
BT-03 화합물에 대하여 계산한 ED50치는 103mg/kg이였고, 나프록센과 이부프로펜의 ED50치는 각각 47.9와 170mg/kg이였다.The ED 50 value calculated for the BT-03 compound was 103 mg / kg, and the ED 50 values for naproxen and ibuprofen were 47.9 and 170 mg / kg, respectively.
그러나 만약 피시험 화합물의 분자량을 고려한다면 나프록센, 이부프로펜 및 BT-03에 대한 ED50치는 각각 0.21, 0.82와 0.29mM/kg이 된다.However, if the molecular weight of the compound under test is considered, the ED 50 values for naproxen, ibuprofen and BT-03 are 0.21, 0.82 and 0.29 mM / kg, respectively.
이러한 관점에서 볼때, BT-03은 나프록센보다 활성이 1.4배나 더 약하고 이부프로펜보다는 활성이 2.8배나 더 강하다. 그러나 이 시험에 사용된 투여량으로 반복해서 투약하면, 나프록센은 BT-03보다 독선이 3.8배나 강하며 이부프로펜보다는 BT-03이 더 낮은 독성을 갖는다.From this point of view, BT-03 is 1.4 times weaker than naproxen and 2.8 times stronger than ibuprofen. However, repeated dosing at the doses used in this test results in naproxen having 3.8 times stronger self-testing than BT-03, and BT-03 having lower toxicity than ibuprofen.
(B) 쥐에 있어서 프로인트 보조액(Freund adjuvant)에 의해서 관절염의 억제.(B) Inhibition of arthritis by Freund's adjuvant in rats.
(Newbould B.B. Brit. Journ. of Pharmacol. 21,127, 1963참조).(See Newbould B.B.Britt Journ. Of Pharmacol. 21,127, 1963).
BT-03 화합물과 대조물질인 이부프로펜은 모두 주사한 발에 있어서 프로인트 보조액에 의해 직접적으로 발생하는 병변을 억제한다. 부어오른 발의 부피를 50%까지 감소시켜 주는 투약량을 의미하는 BT-03의 ED50치는 87mg/kg이다. 몰비율로 계산하면, 이것은 BT-03에 대하여 0.25mM/kg에 해당하며, 이부프로펜에 대해서는 ED50치가 0.30mM/kg이다.Both the BT-03 compound and ibuprofen, a control compound, inhibit lesions directly induced by Freund's auxiliary solution in the injected foot. The ED 50 value of BT-03 is 87 mg / kg, which means a dosage that reduces the volume of swollen feet by 50%. Calculated in molar ratio, this corresponds to 0.25 mM / kg for BT-03 and an ED 50 value of 0.30 mM / kg for ibuprofen.
결과적으로, BT-03과 대조물질은 모두 프로인트 보조액의 제2병변 특성의 발생을 억제할 수 있지만, 투약량에 비레해서 본 발명의 화합물은 이부프로펜에 비해서 활성이 우수하고 독성이 더욱 낮았다.As a result, although both BT-03 and the control substance can suppress the occurrence of the second lesion characteristic of the Freund's auxiliary solution, the compound of the present invention has better activity and lower toxicity than ibuprofen in terms of dosage.
(C) 새앙쥐에 있어서 초산에 의해서 발생하는 “긴장”에 대한 진정작용.(C) Sedation of the "tension" caused by acetic acid in birds.
(Fennessy M.R., Lee C.R. “Meghods in Narcotic Research” Eds. Ehrenpreisee Neidle Dekker New York 1975 참조).(See Fennessy M.R., Lee C.R. “Meghods in Narcotic Research” Eds. Ehrenpreisee Neidle Dekker New York 1975).
화합물 BT-03은 투약량에 비례해서 초산에 의해서 생기는 긴장을 억제하였다.Compound BT-03 inhibited the tension caused by acetic acid in proportion to dosage.
ED50의 계산치는 123mg/kg이였다. 이부프로펜의 ED50치는 105mg/kg이다.The calculated value for ED 50 was 123 mg / kg. The ED 50 value of ibuprofen is 105 mg / kg.
그러나, 서로 다른 분자량을 고려한다면, 관련된 ED50치 사이의 비율은 BT-03이 이부프로펜보다 활성이 약 1.4배 더 큰 것으로 나타났으며, 그 이유는 몰비율에 근거할때, BT-03의 ED50은 0.35mM/kg에 해당하고, 대비화합물의 것은 0.50mM/kg이기 때문이다.However, considering the different molecular weights, the ratio between the related ED 50 values showed that BT-03 was about 1.4 times more active than ibuprofen, because the molar ratio of ED-based ED 50 corresponds to 0.35 mM / kg and that of the contrasting compound is 0.50 mM / kg.
(D) 쥐에 있어서 플리치-점프 시험(Flinch-jump test)에서의 진정작용.(D) Sedation in the Flinch-jump test in rats.
BT-03 및 이부프로펜은 모두 투약량에 비례해서 체온저하 한개치를 증가시킨다.Both BT-03 and ibuprofen increase one hypothermia in proportion to dosage.
(Turner R.A. “Screeing Methods in Pharmacology” Academic Press-New York 1965 참조).(See Turner R.A. “Screeing Methods in Pharmacology” Academic Press-New York 1965).
체온저하 자극을 50% 증가시키는 투약량으로 정의되는 화합물 BT-03의 ED50치는 129mg/kg이고, 이부프로펜의 ED50치는 108mg/kg이다.The ED 50 value of compound BT-03 is 129 mg / kg and the ED 50 value of ibuprofen is 108 mg / kg, which is defined as the dose that increases the hypothermic stimulation by 50%.
그러나, 이들 두 ED50치의 비교에 있어서 몰비율로 근거한다면(BT-03과 이부프로펜은 각각 0.37mM/kg과 0.52mM/kg임), BT-03의 활성이 데비물질보다 약 1.4배 더 높은 것으로 나타났다.However, based on the molar ratio of these two ED 50 values (BT-03 and ibuprofen are 0.37 mM / kg and 0.52 mM / kg, respectively), the activity of BT-03 was about 1.4 times higher than that of debates. appear.
한편, 이 시험에서 사용한 투약량으로 반복해서 투약한 결과, 이부프로펜이 화합물 BT-03보다 독성이 더 강한 것으로 나타났다.On the other hand, repeated dosing with the dosage used in this test showed that ibuprofen was more toxic than compound BT-03.
우에서 간단히 나타낸 바와 같이, 화합물 BT-03에 대한 약리학적 및 약력학적인 성상의 일반적인 견해는 의외로 유리산보다 적절히 개량된 성상을 나타냄을 입증해 주고 있다.As briefly shown in the text, the general view of the pharmacological and pharmacodynamic properties of compound BT-03 surprisingly demonstrates that it exhibits an adequately improved property than free acid.
확인하기 위하여, 다음 표 3에 28일동안 아급성 독성시험에서 발견된 독성 투약량 TD50치와 상기 시험에서 발견된 유효투약량 ED50치 사이의 비교시험에서 얻어진 치료지수를 나타냈다.To confirm, Table 3 shows the therapeutic index obtained from the comparative test between the toxic dose TD 50 found in the subacute toxicity test for 28 days and the effective dose ED 50 found in the test.
화합물 BT-03의 일정한 잇점을 관찰할 수 있다.Certain advantages of compound BT-03 can be observed.
[표 3]TABLE 3
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IT23601 | 1980-07-22 | ||
IT23601/80A IT1193955B (en) | 1980-07-22 | 1980-07-22 | AMID DERIVATIVES OF P-ISOBUTYLPHENYLPROPIONIC ACID, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
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KR830006185A KR830006185A (en) | 1983-09-20 |
KR840001072B1 true KR840001072B1 (en) | 1984-07-31 |
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KR1019810002639A KR840001072B1 (en) | 1980-07-22 | 1981-07-21 | Process for the preparation amide of p-isobuthy phenyl propionic acid |
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JP (1) | JPS5742663A (en) |
KR (1) | KR840001072B1 (en) |
AR (1) | AR226734A1 (en) |
BE (1) | BE889699A (en) |
BR (1) | BR8104728A (en) |
CA (1) | CA1181419A (en) |
CH (1) | CH648292A5 (en) |
DE (1) | DE3128676C2 (en) |
ES (1) | ES8204414A1 (en) |
FR (1) | FR2491456B1 (en) |
GB (1) | GB2080797B (en) |
IN (1) | IN153746B (en) |
IT (1) | IT1193955B (en) |
LU (1) | LU83497A1 (en) |
MX (1) | MX7038E (en) |
PT (1) | PT73400B (en) |
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US4536346A (en) * | 1983-05-06 | 1985-08-20 | American Cyanamid Company | Aralkanamidophenyl compounds |
HU198446B (en) * | 1987-09-25 | 1989-10-30 | Richter Gedeon Vegyeszet | Process for production of new amids of buten acid and medical compositions containing such active substances |
IT1317826B1 (en) * | 2000-02-11 | 2003-07-15 | Dompe Spa | AMIDES, USEFUL IN THE INHIBITION OF THE CHEMOTAXIS OF NEUTROPHILES INDUCED BY IL-8. |
IT1318466B1 (en) * | 2000-04-14 | 2003-08-25 | Dompe Spa | R-2- (AMINOARYL) -PROPIONIC ACIDS AMIDES, USEFUL IN THE PREVENTION OF LEUKOCYTIVE ACTIVATION. |
ITMI20010395A1 (en) * | 2001-02-27 | 2002-08-27 | Dompe Spa | OMEGA-AMINO ALKYLAMIDS OF R-2-ARYL-PROPIONIC ACIDS AS INHIBITORS OF CHEMOTAXIS OF POLYMORPHONUCLEATED AND MONONUCLEATE CELLS |
EP1457485A1 (en) | 2003-03-14 | 2004-09-15 | Dompé S.P.A. | Sulfonic acids, their derivatives and pharmaceutical compositions containing them |
-
1980
- 1980-07-22 IT IT23601/80A patent/IT1193955B/en active
-
1981
- 1981-07-14 GB GB8121623A patent/GB2080797B/en not_active Expired
- 1981-07-17 CA CA000381957A patent/CA1181419A/en not_active Expired
- 1981-07-20 DE DE3128676A patent/DE3128676C2/en not_active Expired
- 1981-07-20 PT PT73400A patent/PT73400B/en unknown
- 1981-07-20 LU LU83497A patent/LU83497A1/en unknown
- 1981-07-20 IN IN809/CAL/81A patent/IN153746B/en unknown
- 1981-07-21 CH CH4755/81A patent/CH648292A5/en not_active IP Right Cessation
- 1981-07-21 AR AR286159A patent/AR226734A1/en active
- 1981-07-21 ES ES504156A patent/ES8204414A1/en not_active Expired
- 1981-07-21 KR KR1019810002639A patent/KR840001072B1/en active IP Right Grant
- 1981-07-21 JP JP56113098A patent/JPS5742663A/en active Pending
- 1981-07-21 MX MX819564U patent/MX7038E/en unknown
- 1981-07-22 FR FR8114252A patent/FR2491456B1/fr not_active Expired
- 1981-07-22 BR BR8104728A patent/BR8104728A/en unknown
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Also Published As
Publication number | Publication date |
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IN153746B (en) | 1984-08-18 |
ES504156A0 (en) | 1982-05-16 |
BR8104728A (en) | 1982-04-13 |
DE3128676C2 (en) | 1983-12-01 |
GB2080797B (en) | 1984-01-18 |
LU83497A1 (en) | 1981-10-29 |
KR830006185A (en) | 1983-09-20 |
BE889699A (en) | 1981-11-16 |
GB2080797A (en) | 1982-02-10 |
ES8204414A1 (en) | 1982-05-16 |
CH648292A5 (en) | 1985-03-15 |
FR2491456B1 (en) | 1985-11-15 |
PT73400A (en) | 1981-08-01 |
PT73400B (en) | 1982-10-01 |
FR2491456A1 (en) | 1982-04-09 |
AR226734A1 (en) | 1982-08-13 |
CA1181419A (en) | 1985-01-22 |
IT1193955B (en) | 1988-08-31 |
IT8023601A0 (en) | 1980-07-22 |
MX7038E (en) | 1987-03-18 |
DE3128676A1 (en) | 1982-04-22 |
JPS5742663A (en) | 1982-03-10 |
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