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PGE1 Analogs

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PGE1 Analogs Patentamt JEuropaischesEuropean Patent Office Office europeen des brevets © Publication number : 0 574 1 85 A2 @ EUROPEAN PATENT APPLICATION (2j) Application number : 93304330.9 © int. ci.5: C07C 405/00, //A61K31/557 (22) Date of filing : 03.06.93 (§) Priority : 08.06.92 CH 570/92 (72) Inventor : Mammarella, Carlos Alberto Genaro Gregorio de Laferrere 1593-20 Piso Buenos Aires Date of of (AR) (43) publication application : Inventor Carlos Alberto 15.12.93 Bulletin 93/50 : Buschi, Esteban de Luca 2244 Buenos Aires (AR) @ Designated Contracting States : Inventor : Giarcovich, Silvia Susana AT BE CH DE DK ES FR GB GR IE IT LI LU NL Pacheco de Melo 2046-1 o "2" PT SE Buenos Aires (AR) © Applicant : NEWPHARMA INTERNATIONAL @ Representative : Pearce, Anthony Richmond CORPORATION MARKS & CLERK Alpha Tower Suffolk Street Juncal 1305, Of. 1201, Queensway Birmingham B1 1TT (GB) Montevideo (UY) (54) PGE1 analogs. 57 A compound which is an alkyl ester of trans- -1 5-deoxy-1 6-hydroxy-1 6-methyl PGEi, characterised by the formula : OR CVll in which R represents a CrC4 alkyl group, preferably methyl, ethyl or isopropyl, is useful as a medicament to stimulate uterine contractions. Intermediates and methods of preparing same and CM converting such intermediates to the final product are also disclosed. if) 00 "<t ro- ll) O Q_ LU Jouve, 18, rue Saint-Denis, 75001 PARIS EP 0 574 185 A2 This invention relates to the discovery of a unique molecule as part of a project for the preparation of series of prostaglandin analogs with a specific uterotonic activity for the induction of labor at term. These molecules are analogs of PGE^ specifically designed for use in the induction of labor at term and have a short duration of action in order to minimize the adverse reactions to mother and fetus. 5 The molecule backbone could be substituted by different groups leading to different derivatives (Formula I)- With Ri = H, alkyl or cycloalkyl radical, linear or branched. R2 = H or silyl derivative or cyclic ether (ie: THP derivative). 20 The PGEi analog presented in this invention shows uterotonic properties, enhancing the response to PGF2a in isolated rat uterus. The drug possesses other pharmacological properties as inhibitor of gastric acid secretion, hypotensive and bronchodilator. Review: The product described in the present invention is a PGE^ analog. Natural prostaglandins are ali- cyclic compounds related to the prostanoic acid structure (Formula II). 25 It is useful to bear in mind the following statements related to natural products connected chemically and biologically to the molecule described in this invention. Eicosanoids : Are biologically active substances derived from polyunsaturated C-20 fatty acids and include prostaglandins and leukotrienes. Prostanoids: Are metabolic products derived from polyunsaturated fatty acids, mainly arachidonic acid (III). 30 This transformation is catalyzed by the fatty acid cyclooxygenase-peroxidase. These compounds are extreme- ly potent mediators of a diverse group of physiologic processes. 35 " 15 j? 19 II 12 11 IS II III 40 Natural prostaglandins: Are related to prostanoic acid (II) and result of either reductive or disproportionate cleavage of the peroxy linkage of the endoperoxide products produced by the fatty acid cyclooxygenase-per- oxidase. In natural prostaglandins, positions 13 and 14 are bonded by a trans double bond and position 15 has a 45 hydroxyl group with alpha configuration. The upper side chain is attached to a cyclopentane ring with a configuration (below the ring plane) and the lower side chain has a p configuration (above the ring plane). Both chains have a trans configuration with respect to the cyclopentane ring. Prostaglandins have different substituents, in the cyclopentane ring and are classified according to the so substitution on the cyclopentane ring and according to the number of double bonds present in the upper and lower side chains. In accordance with the substitution on the cyclopentane ring, different types of prostaglan- dins are obtained. A, E, F, G, I and J (Figure A). 55 2 EP 0 574 185 A2 15 PG HyG PG I, PG J 20 Figure A The distinction between prostaglandins A and G lies outside the cyclopentane ring. Prostacycline or PGI2 has an additional oxolane ring (an ether linkage from C-9 to C-6) but nonetheless is considered as prostaglan- 25 din and can be named as a 6,9-a-oxoprostanoic acid derivative. The location and number of double bonds between C5-C6; C13-C14 and C17-C18 defined three subtypes of prostaglandins. A trans-double bond at C13-C14 defines the series 1 (IV) and is indicated by a subscript 1 written below the letter that defines the prostaglandin type (ie: prostaglandin or PGA^. 30 The presence of both a trans-double bond at C13-C14 and a cis-double bond at C5-C6 define series 2 Pros- taglandins (V) and is indicated with a subscript 2 (ie: PGE2). Finally, a trans-double bond at C13-C14, a cis-double bond at C5-C6 and a cis-double bond at C17-C18, define the series 3 (VI) and is indicated with a subscript 3. 1 40 Series 2 45 Series 3 This nomenclature, based on type and series definition uses trivial names of prostaglandins and designa- tes analogs by modification of the trivial names [J.Med. Chem. 17, 911 (1974)]. Another system follows rules of the "International Union of Pure an Applied Chemistry" (IUPAC) or the 3 EP 0 574 185 A2 "Chemical Abstracts" (CA). The first one names prostaglandins as derivatives of heptanoic acid and the second one as derivatives of prostanoic acid. The trivial name of structure VII is prostaglandin or PGF1a in the IUPAC system: 7-[3R,5S-dihydroxy- 5 2R-(3S-hydroxy-1E-octenyl]-cyclopent-1R-yl] heptanoic acid and in the CA system: (9a, 11a, 13E, 15S)- 9,11,1 5-trihydroxy-prost- 1 3-en- 1 -oic acid . The Cahn-lngold-Prelog system [(Angew. Chem. Int. Ed. Engl. 5, 385 (1966)] defines the stereochemistry of any asymmetric center and the a,p designation of the asymmetric carbons is still in use. The double bond configuration is designed by the use of prefixes cis or trans or the equivalents Z or E. 20 Prostaglandins have ubiquitous distribution in animal tissues and promote both physiological and patho- physiological effects in mammals. They have diverse pharmacological effects on the cardiovascular system, gastrointestinal, circulatory and smooth muscle. Prostaglandins E and A are potent vasodilators for most species and in most vascular beds (except in big veins) where PGF2a shows greater species variation. PGE's and PGA's initially lower arterial blood pressure 25 and consequently the peripheral resistance. This action promotes an increase of the cardiac output and organs blood flow. PGEi, PGD2 (0.1 nM) and PGI2 (1 to 10 nM) inhibit platelets aggregation "in vitro". PGA, PGE, and PGE2 induce erythropoietin release from the kidney cortex producing an increase on the erythropoiesis. The effects of prostaglandins on smooth muscle are diverse: PGE2 and PGI2 inhibit histamine release from 30 basophilic leukocytes. Prostaglandins of the F series contract tracheal and bronchial smooth muscle whereas prostaglandins E relax these muscles. PGI2 is hypotensive for most species, including humans. PGF's type contract human non-pregnant uterine smooth muscle strips whereas prostaglandins type A, E and B relax these muscles. PGF and PGE2, at low concentrations, contract pregnant uterine muscle strips while PGI2 and high con- 35 centrationsof PGE2 relax the uterine muscle. The intravenous administration of either PGE2 or PGF2a produces a dose-dependent increase of the frequency and intensity of the contraction of the pregnant human uterus. Some prostaglandins induce cervical ripening and softening when locally administered. Prostaglandins of E and F series contract the longitudinal muscle "in vitro" from the stomach to the colon whereas PGF contracts and PGE relaxes circular smooth muscle. 40 The administration of PGE causes diarrhea, cramps, biliary reflux and nausea when administered as abor- tifacient for the termination of pregnancy. Finally, prostaglandins E and l2 inhibit both the gastric acid and pepsin secretion stimulated by feeding, histamine, acetylcholine- and gastrin-induced secretions. Prostaglandins also increase both mucous, water and the electrolytes secretion from the digestive tract. This could result in diarrhea and abdominal cramps, 45 often at therapeutic dosages. As a consequence of their multiple pharmacological effects, prostaglandins and their analogs have broad and diverse therapeutic uses. PGE'sand PGF's may be used in obstetric and gynecology for abortion and labor induction. In gastroenterology they are used either to treat peptic ulcers ordisorders involving motility, secretion or absorption in the gastrointestinal tract. They are also useful bronchodilators, as anticlotting agents and for so the treatment of circulatory diseases such as hypertension, peripheral vascular diseases and cardiac disor- ders. There are more complete information related to the properties and actions of these compounds in the fol- lowing references: [Ann. N. Y. Acad. Sci., 180: 1 (1971); J. Am. Med. Assn., 53: 92 (1972); "Prostaglandinas y Compuestos Relacionados" (1989), El Ateneo Ed., Bs. As.; "The Pharmacological Basis of Therapeutics" 55 (1990), Gillman, Rail, Nies, Taylor Eds., Pergamon Press, New York]. DESCRIPTION OF PRIOR ART Until now, no PGE^ analog was introduced to human therapeutics for the induction of labor at term. Listed 4 EP 0 574 185 A2 below are all available data on prior art that are relevant to this invention: A) The first prior art to consider in the present patent refers to the drugs employed with the objective of stimulating the uterine contractions in the following clinical settings: a) induction or promotion of labor, b) 5 control of postpartum bleeding and uterine atonia, c) inducing uterine contractions after a cesarean section or during uterine surgery and d) induction of therapeutic abortions.
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