PROSTAGLANDIN DERIVATES, THEIR PROCESS AND PHARMACEUTICAL COMPOSITIONS

Abstract: Novel prostaglandins of formula (IA) and (IB) are described wherein: n = 2, 3; m = 4, 5, 6, 7; p = 5, 6, 7, Y, when X = H, -NH2, represents -NH-NH2, -CH2NH2, -NRR', wherein R and R' may be the same or different, each representing: H, a linear or branched alkyl, alkenyl, alkynyl, phenyl, substituted aryl; or, taken together with the substituent X, it may constitute the hydantoin nucleus, and Z = -CN, -CH2NH2, -CH2OH, -CHO, (a), -COCH3, (b), COW, wherein R and R' have the meanings given above and W may be -OR, -NRR'. Furthermore, the instant invention also concerns the use of the novel prostaglandins as a pharmaceutical composition having antiulcer activity.

Description: - 1 - Prostaglandin derivates, their process and pharmaceutical compositions. DESCRIPTION The present invention relates to compounds having a 5 prostaglandin -like structure and processes for the prepara tion thereof. Furthermore, the instant invention relates also to phar¬ maceutical compositions having antiulcer activity. The most modern treatments of peptic ulcers tend, on the _ one hand, to promote protective factors of the mucose where¬ as on the other they tend to moderate the acid or pepsine secretion, i.e. the aggressive agents. Recently, some prostaglandin derivatives have been com¬ mercialized which possess both these characteristics: 5 misoprostol (BE patent 827,127 of G.D.Searle & Co.,Chicago, 111.) and, particularly in Italy, rosaprostol (IT patent 1,060,366 - issued on July 10,1982 owned by the Applicants). The Applicants ' too ha.ve continuted the study of new prostaglandine derivatives and have discovered that some 0 functional changes to the structure of rosaprostol led to derivatives having a. more potent citoprotective and anti- secretory activity than that possessed by the cited rosa¬ prostol. These new discoveries are the subject matter of the IT patent application No. 22358 A/85. Following along this route, it has now surprisingly been found that modifications in the cyclopentene ring and/or in the functional group at position 1 lead to derivatives pos¬ sessing a high antiulcer activity. These new compounds correspond to one of the following formulae: SUBSTITUTE $rι&ι- » ( IA) ( 13) wherein: n = 2 , 3 ; m. = 4, 5 , 6 , 7 ; p = 5 , 6 , 7 ; Y, in the case where X = H, -NH , represents -NH-NH , -CH NH , -NRR 1 , wherin R and R' may be the same or different, each representing: H, a linear or branched alkyl τ alkenyl, alkynyl, phenyl, substi¬ tuted aryl; or,taken together with the substituent X, ' it may constitute the hydantoin ring (as in com- pounds (IIA) or (IIB), -indicated purely for illus¬ trative purposes). (IIA) (113) Z = -CN, -CH 2 NK 2 , -CH 2 0H, -CHO, -CH -—OR -COCH CH. ^QR' -C COW, OR 0R r wherin R and R' have the meanings given above and W may be -OR, -NRR' . The compounds of formula (IA) wherein : n =2; m = 5; - p = 6, X = H; Y = -NRR 1 (R and R* having the meanings given SUBSTITUTE πo- ' - above ) ; and Z = -C-0 II 0 wherein Q = -OH, (C -C )-alkoxy, phenoxy, benzyloxy or NHR" (wherein R" is. (C -C )-alkyl or H) are the subject matter of IT 1060366 and of the Italian patent application 22358 A/8(of the Applicants and therefore they are not claimed in the present application.) The present invention includes also cationic pharma- ceutically acceptable salts of the compounds of formula (IA) and (IB) when W = -OH and, in general, the pharmaceutically acceptable anionic salts of said compounds. The expression "pharmaceutically acceptable cationic salts" refers to the alkali and alkaline earth metal salts such as, e.g. sodium, potassium, calcium, magnesium or salts of aluminum, ammonium, zinc and organic amines, such as e.g. triethanolamine, and also aminoacids such as e.g. lysine, arginine.phenylalaline and proline, inner salts and salts of basic resins. The expression "pharmaceutically acceptable anionic salts" refers to salts obtained by the addition of an inor¬ ganic acid such as, e.g. hydrochloric, hydrobromic, nitric, phosphoric, sulphuric, or of an organic acid, such as e.g. benzene—sulfonic, benzoic, citric, laurylsulfonic, fumaric, oxalic, maleic, methanesulfonic, tartaric, ascorbic, p-toluenesulfonic,_ salicylic and succinic acid. With poly- basic acids, the salt may include more than one mole of base per mole of acid. However, the salts obtained from one mole of acid per mole of the inventive compound are preferred. The antiulcer activity of the compounds of the instant invention is evaluated by the ethanol induced ulcers, by the * • hydrochloric acid induced ulcers and by the influence of the gastric secretion in the rat. The compounds of the present Invention can be prepared according to the reactions known in the art and the reaction schemes of which, are outlined hereinafter only for illus¬ trative purposes. 1) The compounds of formula (IA) and (13) wherein: - n, m, p have the meanings given above, - X = H, NH ; Y = NH-NH , CH NH , NRR' , wherein R and R' carL be the same or different, each representing H, a linear or branched alkyl, alkenyl, alkynyl, substituted aryl ,and - Z has the meanings given above, can be prepared starting from the ketones of formula (IIIA) and (III.B. ) respectively, according to per se known reac¬ tions such as, e.g. reductive aminations (with K and metal catalysts rather than with hydrides of different metals) or the introduction of C -units by means of the Wittig reac¬ tion using triphenyl-phosphonium ethoxymethylide (0 P=CH-0CH ) , hydrolysis of vinyl ether, reduction to alcohol, preparation of the corresponding mesylate, reaction with N and reduction to amine, or else by reducing the O ketone to alcohol, preparing the mesylate, substituting with NaN and reducing same. The reductive amination is shown in the following reaction schemes (schemes IA and IB). SCHEME IA SCHEME IB ( (IIIB: (IVB) 2) The compounds of for ula(lA) and (IB) wherein X and Y, taken to-gether, form a hydantoin ring, while n, m, p and Z have the meanings given above, are prepared from ketones (IIIA) and (IIIB) respectively by reacting with cyanide salts under controlled pH (reactions schemes 2A and 2B): SCHEME 2A SCHEME 2B (IIIB) (VB) - 6 - The efficacy of the compounds of the instant Invention as antiulcer agents has been determined by means of the following tests: i) Ξthanol induced ulcers in the rat The tests were carried out according to what has been described in literature (A. Robert et al. Gastroenterology 77, 433 (1979) (Table 1) ii) Hydrochloric acid induced ulcers in the rat The tests were carried out according to what has been described in literature (A.Robert et al. Gastroenetrology 77, 433 (1979) ) (Table ). iii) Influence on the gastric secretion in the rat The tests were carried out according to what has been described in literature (Shay et al. Gastroenterology 5, 43, (1945) (Table 3) . iv) Cytoprotective activity in the rat The tests were carried out according to what has been described in literature: 1 (A.Robert et al- Gastroenterology, 77, 433 (1979)) (Table 4) 2 (Szabo et al. Sciene 214 (200) (1981)) (Table 4) SUBSTITUTE fcnc- continuation T A B L 1 SUBSTITUTE SHfcε T A B L E 2 HYDRO C HLORIC ACID INDUCED ULCERS IN THE RAT SUBSTITUTE SH££H TA3LE 3 Gastric Secretion after two hours Cytoprotective activity DE mg/kg TABLE &■ The cytoprotective anc' an-tisecretat -5 /e act:, xty shown by the inventive compounds in the ref rred tests reflects the usefulness of the drugs subject of the present invention in the treatment of peptic ulcers in mammals, including man. The compounds of the present invention are preferably administered as pharmaceutical.compositions, in admixture with one or more pharmacologically acceptable diluents and/ or excipients. Within the scope of the present description the term "pharmacologically acceptable diluents and/or excipients" refers to .substances such as,e.g. amides and derivatives thereof (maize and rice starch,carboxymethyl starch),cellu- lose and its derivatives(such as AVICΞL , registered trade¬ mark of FMC Corporation of Philadelphia,U.S.A. , and methyl- cellulose, ethylcellulose, hydropropyl-metnyicellulose) ; silicates and silicone oxides (talc, hydrated calcium silicate, Mg and Al silicates, AEROSIL . } registered trade- mark of Wacker ' -Chemie GmbH, Munich,FRG, SYLOID (R), registered trademark of W.R.Grace & Co., New York, U.S.A.); solid ionic surfactants (sodium laurylsulphate) and non-ionic sur¬ factants (such as esters of saccarose with fatty acids); acrylic derivatives and the polymers thereof; alkali and alkaline earth metal sulphates, carbonates and phosphates; polyvinyl pyrrolidone and derivatives thereof. They are preferably administered orally in the form of tablets, granules, syrups, etc. or perenterally (i.v. or i.m.). Although the dosage can vary according to the symptoms, sex, body weight and conditions of the patient and also according to the frequency of the route of administration, the inven¬ tive compounds can be orally administered to an adult at a daily dosage of from 0.1 to 3000 mg,preferably at from 1 to 2000 mg in a single dose or in subdivided doses over 24 hours. Example 1 2-(7-hydrσxyheptyl)-3-(hexyl)-cyclopentylamine (formula (IA)), herein n= 2, m = 5, p = 6, X = H, Y = NH^ Z =CH OK; (compound IB -P-01023) . A suspension of LiAlH (2.3 g) in ethyl ether (400 ml) is added dropwise, under argon, with a solution of 2-(carobxylhexyl)-3-hexyl-cyclopentylamine (15 g) in ethyl ether (100 ml, keeping the temperature at +25°C. The reaction mixture is stirred for 3 hours. It is then cooled to 0°C and added dropwise with ethyl acetate (40 ml). and thereafter water (100 ml) is cautiously added whereupon the phases are separated. The organic phase is washed to neutral- ity an d anhydratsd,evaporated to dryness under reduced pres¬ sure, yielding the title compound (12.3 g) . Analysis: I.R. (\) max) : . - 3340 cm 1 H- MR : 3.8 ~ 3.3 (m, 3H.) ; 2.1 (s, 3H) ; 1.8 ÷ 0. (broad, 31H) Equivalent weight = 309.1 (=96%) Elemental analysis: calculated found c 76.32 76.1 H 13.07 12.96 N 4.94 5.01 Example 2 5-spiro-_2-(6-carboxy-ethyl)-3-hexyl-cyclopentyl/- imidazoline-2,4-dione (formula (IA)), wherein n= 2, m = 5, p = 6; X and Y represent the hydantoin nucleus; Z = COOK; (IBI-P-01028) . SUBSTITUTE Shtic A solution of KCN (18 g) and (NH ) CO (84 g) in water (450 ml) is added with a solution of the sodium salt of 9- oxo-bis-nor-prostanoic acid (90 g) in water (450 ml). The reaction mixture is heated for 5 hours at 80°C under stir- ring. It is then cooled to 0 ÷ 5°C and acidified with 6N HC1 at pH = 2. The acid solution is extracted with ethyl ether (300 ml x 3), washed with water to neutrality and anhydrated. The solution is evaporated to dryness whereupon a semi-solid is obtained which is washed repeatedly with hexane and crystallized from 8 : 2 ethyl ether/hexane. 55 g of white crystalline compound is obtained. Analysis: I.R. :3250,3200,3140,3020,.1700, 1750, 1720,1675, 1460 cm "1 " " " H-NMR: 9.4 (s, 1H) ; 7.3 (s, 1H) ; 2.35 (m, 4H) ; 1.4(broad, 24 H) ; 0.95 (t, 3H) Example 3 2-(7-hydroxy-heptyl)-3-hexyl-cyclopentanol A solution of 9-oxo-bis-nor-prostanoic acid (308 g) in THF (3 1) is added with triethylamine (168.5 ml). The reac¬ tion mixture is brough ,under stirring, o -30°C and added dropwise with ethyl chloroformate (109 ml) in 15 minutes whereby the temperature is allowed to rise to 0÷+5°C,then keeping said temperature for 30 minutes. The salts are filtrated by means of a Buchner filter and the filtrate is added dropwise into a solution of NaBH (198 g) in water (2 1), while the temperature is kept at +10 - 15°C,in about 30 minutes. At the end, the reaction mixture is stirred for 30 minutes at +15°C and the salts are filtered once more, UTESnti I - 14 - the phases are separated and she liquor is extracted with ethyl ether (500 ml). Subsequently, the combined organic phasesare washed with a saturated NCI solution and evaporated to dryness under reduced pressure. 238 g of a clear oil is obtained. I.R. (\) max): 3330 cm " Example 4 2-(7-oxo-heptyl)-3-hexyl-cyclopentanol A solution of the compound of example 3 (100 g) in methylene chloride (360 ml) is added with KBr (1.15 g), 2,2,6,6-tetramethyl-piperidine-l-oxide (TEMPO,0.275 g) . The reaction mixture is then cooled to -5°C and added drop¬ wise with a 0.5M sodium hypochloride solution which has been previously saturated with NaHCO (861 ml), keeping the temperature at +5 V+10°C. The reaction mixture is then left at 15°C for 1 hour and the phases are separated. The organic phase is washed with water, anhydrated and evaporated under reduced pressure. 102.9 g of a fluid oil is obtained. I.R. (Λ) max ): 2270, 1720 cm " Exa ole 5 3-hexyl-2-(6-cyano-ethyl) cyclopentanol formate A solution of the compound according to Example 4 (102 g) in HCOOH (500 ml) is added at room teπroerature with SUBSTITUTE SHfcfc ι hydroxyla ine hydrochloride (32 g) . The reaction mixture is then heated to 50°C and stirred for 30 minutes. It is evapo¬ rated under reduced pressure to a small volume and poured into water (800 ml), added with ethyl ether (800 ml) and the pH is adjusted to neutrality with 10% NaOH. The ethereal phase is separated and washed with water to neutrality. It is then anhydrated' and evaporated, yielding a dense dark oil (100 g) . Said oil is taken up with formic acid (600 ml) and heated at 40°C for 40 minutes. The reaction mixture is then evaporated to dryness,under reduced pressure, it is taken up with ethyl ether(500 ml) and washed with a water/ saturated sodium chloride solution up to neutrality.- . The reaction mixture is anhydrated and the solvent is evapo¬ rated. A yield of 105 g (brown oil) is obtained. I.R. ( > max ): 2220, 1740 cm " Example 6 3-hexyl-2-(6-cyano-hexyl)-cyclopentanol The compound of Example 5 (105 g) dissolved in methanol (1500 ml) is added with a K CO (44 g) solution in water (250 ml) and stirred for 40 minutes. The reaction mixture i S concentrated to a small volume, under reduced pressure, added with water and extracted with ethyl ether (500 ml). The extract is washed with water up to neutrality,it is then anhydrated and the solvent is evaporated. 96 g of a dense oil is obtained which is then chromatographed on silica gel, eluting with a 7 : 3 n-hexane/ethyl acetate mixture, thus yielding 81 g of the title compound. - 15 - Analysis : -i I.R. ( max): 3400, 2220 cm ^H-NMR : 4.2 ( , 1H) ; 2.3 (t, 2H) ; 2 (s,lH); 0.3 (t,3H; Example 7 3-hexyl-2-(6-cyano-hexyl)-cyclopentyl-azide A solution of the compound according to Example 6 (60 g) in me hylene chloride (600 ml) is added with triethylamine (45.5 ml). The reaction mixture is then cooled to 0°C and added dropwise with a mesylchloride solution (21 ml), in methylene chloride (100 ml) in 20 minutes. The reaction mixture is then kept 30 minutes at a temperature of 0÷÷5°C and poured into water (800 ml). The phases are separated and the organic phase is washed with water to neutrality. It is anhydrated and evaporated yielding 78 g of a clear _1 oil (I.R. = 2220 cm ). The oily residue is then taken up with water (160 ml), added with NaN (35 g), hexadeciltri- butyl-fosfonium bromide (16 g) and stirred at 75°C for 4 hours. At the end, it is cooled and extracted with ethyl ether (500 ml). The organic phase is washed with water and anhydrated. The solvent is evaporated at reduced pressure, yielding 71 g of a dense oil. After silica gel chromato- graphy, using a 9 : 1 hexane/ethyl acetate eluent, 40 g of the title compound is obtained. I.R. (\) max) : 2100, 2200 cm " Example 8 3-hexyl-2-(6-cyano-hexyl)-cycLopentylamine. Derivative of formula (IA) wherein : n = 2; m = 5; p = 6; X = H; Y =NK ; Z = CN (compound IBI-P-01037) . The compound according to Example 7 (20 g) dissolved in methanol (500 ml) is added with 5% palladium on carbon(2g). The reaction mixture is then subjected to hydrogen atmosphere and stirred for 4 hours at room temperature. At the end, the catalyst is filtered off and the ' solvent is evaporated under reduced pressure. 18 g of the title compound. is obtained. Analysis I.R. ( max) : 3300, 2200 cm "1 Titre as base = 95% Elemental analysis: calculated found c 77 . 63 77 . 17 H 12 . 31 12 . 24 N 10 .06 9 . 84 ExamDle 9 3-hexyl-2-(6-diethoxymethyl-hexyl)-cyclopentanol The compound according to Example 4(80 g) , dissolved in ethanol (800 ml),is added with p-toluene sulfonic acid (2.5 g) and stirred for 1 hour at room temperature. The reac¬ tion mixture is poured into water (i 1) and 5% bicarbonate (100 ml) and extracted with ethyl ether (500 ml). The organic phase is separated and washed with water and anhydrated. Upon evaporation, 92 g of a fluid oil is obtained. I.R. ( \ ) max): 3300 cm Example 10 3-hexyl-2-(6-diethoxymethyl-hexyl)-cyclopentyl-azide UBSTITUTE Sr i *- The compound according to Example 9 (29 g) is handled as described in Example 7 using methylene chloride (300 ml), triethylamine (25 ml), mesylchloride (14 ml), water (280 ml), NaN (14.2 g) , hexadecyl-tributyl-fosfonium bromide (4.4 g), o b taining thereby 27 g of the title compound. I.R. ( C max) : 2100 cm " Example 11 , 3-hexyl-2-(6-diethox methyl-hexyl)-cyclopentyl amine, the compound of formula (IA) wherein : n = 2; m = 5; p = 6; X = H; Y = NH ; Z = CH(OEt) (IBI-P-01053) . The compound of Example 10 (27 g) is handled as described in Example 8 using ethanol instead of methanol (500 ml) and 5% Pd/C (1.5 g).Then 22 g of a fluid oil is obtained which is subjected to " silica gel ' chromatography,eluting with 8:2 CH Cl /ethanol,thus obtaining 14 g of the title compound. Analysis I.R. (^5 max) : 3300, 2200 cm " " H-NMR: 4.2 (t,lH);3.5 (m, 5H) ; 2.2 -J 0.8 ( , 39H) Titre as base = 99% Elemental analysis: calculated found c 74.36 74.21 H 12.67 12.33 N 7.88 8.01 Examole 12 3-hexyl-2-(7-hydroxy-octyl)-cyclopentyl-azide The compound of Example 10 (23 g) is added with acetone (350 ml) and 2N HCl (50 ml). The reaction mixture is stirred at room temperature for 1 hour. Thereafter, the reaction mix¬ ture is added with ethyl ether (300 ml) and water (500 ml). The phases are separated and the organic phase is washed with water to neutrality. The reaction mixture is anhydra¬ ted and evaporated under reduced pressure to give 18 g of an oily residue that is taken up with ethyl ether (180 ml) and treated with a solution of 0.5N CH Mgl, in ether (120 ml at 0°C. At the end of the addition, the reaction mixture is decomposed with, slightly acidified water,and the organic phase is washed with water. The reaction mixture is anhydra¬ ted and evaporated under reduced pressure. 14 g of a clear oil is obtained. I.R. (^ max) : 3360, 2100 cm " Example 13 3-hexy1-2-(7-keto-octyl)-eye1opentyl-azide To the compound of Example 12 (10.2 g) , dissolved in acetone (200 ml) is added dropwise an aqueous solution of the Jones reactive (12 ml) at 0°C.whereaf er the reac- tion mixture is left 15 minutes at 0 ÷ +5°C and it is then poured into a 1 : 1 ethanol/water solution (200 ml). The phases are separated and the ethereal phase is washed with water up to neutrality.The solvent is anhydrated and evapo¬ rated. 9.4 g of a brown oil is obtained. I.R- ( ^ max) : 2100, 1720 cm " Example 14 3-hexyl-2-(7,7'-diethyoxy-octyl)-cyclopentyl-azide STITUTE n&'c- The compound of Example 13, dissolved in n-hexane (980 ml), is added with K 10 ontmorillonite/triethylor:ho- formate (100 g), previously prepared by suspending the rπonr- orillonite (60 g) in triethylorthofor a ' te (70 ml) and fil- tering over Buchner the thus obtained complex which is used in the wet form. The reaction mixture is stirred for 2 hours at room temperature, and the solid is filtered off. The fil¬ tered organic phase is washed with bicarbonate and anhydrated It is evaporated to dryness yielding 10 g of a brown oil. I.R. (ς)max): 2100 cm " . Example 15' 3-hexyl-2-(7,7*-diethyoxy-octyl)-cyclopentylamine, deriva¬ tive of formula (IA) wherein n= 2; m = 5; p = 6; X = H; Y = NH d.; Z = -C(0C d.H_b)-.CH (IBI-P-01055) The compound of Example 14 (10 g) is handled as described in Example 8, using ethanol (150 ml), 5% Pd/C (2g) . At the e_nd of the operation, 8 g of the title compound is obtained. Analysis: -1 I.R. ( max) :.3340 cm X H-NMR : 3.4 (m, 5H) ; 2 •£■ 0.8 (m, 42H) Titer as base = 96% Elemental analysis: lculat :ed found C 74.7 74.42 H 12.81 12. 66 N 3 . 79 3 .91 Example 16 3r-hexyl-2-(6-carbomethoxy-hexyl) -hydroxymethyl-cyclopentane BSTlTUTE πccl Potassium ter-butylate (30 g) is added in one go to anhydrous DMSO (3 1) and stirred until it is completely dissolved, whereupon it is added with methoxymethyl- triphenyl-phosphonium chloride (91.6 g) " . The solution is kept 15 minutes at room temperature. The methyl ester of 9-oxo-nor-prostanoic acid is then rapidly added and the reaction mixture is stirred at room temperature. It is then poured into water (6 1) and IN HCl (0.6 1), extracted with ethyl ether (2 x 4 1) and the ethereal phase is washed with water to neutrality. The reaction mixture is anhydrated and evaporated at reduced pressure. The thus obtained resi¬ due (111 g) is purified by means of silica gel chromatogra- phy eluting with 9 : 1 n-hexane/ethyl acetate, thus obtain¬ ing 31 g of a brown dense oil. Said substance is taken up with acetone (1 1) and 3N HCl (200 ml) and stirred for 1 hour at room temperature. The acetone is evaporated under reduced pressure and the reaction mixture is thereafter ex¬ tracted with methylene chloride, the organic phase is washed with water to neutrality and evaporated at reduced pressure, to give ■ 49 g of a brown oily residue. The thus obtained residue is dissolved in methanol (500 ml) and treated with NaBH (7g) for 1 hour at 0°C. The reaction mixture is evaporated at reduced pressure, up to a small volume, it is added with slightly acid water and extracted with ethyl ether (400 ml). The etheral phase is washed with water and anhydrated. It is evaporated,at reduced pressure.yielding 32 g of the title compound. _1 I.R. ( max): 3200, 1740 cm Examole 17 3-hexyl-2-(6-carbomethoxy-hexyl)-azidomethyl-cyclopentane SHfcϊ: i The compound of Example I 6 " (32 g) is handled as de¬ scribed in Example 7 using CH Cl (300ml) ,N(C H ) (21.5 ml), mes.yl chloride (15ml), water (450 ml) Na (16.6 g) , hexade- cil-tributylphosphonium bromide (5.1 g) . At the end of the reaction, 30 g of the chromatographed compound is* obtained. I.R. (^ max) : 2100; 1740 cm " Example 18 3-hexyl-2-(6-carbomethoxy-hexyl)-aminomethyl-cyclopentane The compound of Example 17 (30 g) is handled as de¬ scribed in Example 8, using methanol (30 g) 5% Pd/C (10 g) . 15.1 g of the compound, chromatographed on silica gel, is obtained and eluted with 8 :. 2 n-hexane/ether. I.R. ( max) : 3300, 1740 cm " Example 19 3-hexyl-2-(6-carboxy-hexyl)-aminomethyl-cyclopentane, com¬ pound of formula (IA) wherein n = 2; m = 5; p = 6; X = H; Y = CH NH ; Z=C00H (IBI-P-01058) . The compound of Example 18 (6.6 g) , dissolved in methanol (80 ml) ,is handled " with a solution of K CO (5.6 g) in water (30 ml) and refluxed for 3 hours. The methanol is evaporated and the solution diluted with water (50 ml) and then the pH adjusted to 5.8 with 6N HCl. The solid white precipitate is filtered off and dessicated under reduced pressure . 5.2 g of the white crystalline title compound is obtained. I.R. ( max) : 2700, 1625, 1530. Titre as base= 93% Elemental analysis : calculate i d found C 73 . 26 73 . 19 H 11 . 97 11 . 95 N 4. 50 4. 62 Example 20 N-/3-hexyl-2-(6-carboxy-hexyl)-cyclopentyl/-N'-(.terbutoxy- carbonyl) )-hydrazine A solution of 9-oxo-19,20-bis-nor-prostanoic acid (29.6 g) in methanol (100 ml) is added with Boc-hydrazine (16 g) dissolved in methanol (100 ml) and stirred for 1 hour at 30°C. Water (400 ml) is added and the phases extrac¬ ted with ether (400 ml). The etheral phase is washed with water (200 ml) and anhydrated. After evaporation, 43.8 g of a solid is obtained with melting point at 107°C. This substance is redissolved in methanol (400 ml) and treated with PtO (2 g) in a small hydrogenator. The reaction mix¬ ture is kept 6 hours under a hydrogen pressure of 4 5 atm. at 60°C. The catalyst is filtered off and the solvent evap¬ orated. The thus obtained crude compound (44.6 g) is chro¬ matographed on silica gel, eluting with 1 : 1 ether/n-hexane T e title compound (35 g) is obtained as a white waxy solid. SUBSTITUTEbni-.-• - 2^ - Analysis -1 I.R. ( max) : 3300, 1710 cm X K-NMR : 1.4 (S; 9H) Elemental analysis: - calculated found C 66.95 66.81 H 10.75 10.86 N 6.79 6.55 Examυle 21 [_ 3-hexyl-2-(6-carboxy-hexyl_)_/-hydrazine hydrochloride, com¬ pound of formula (IA) wherein: n = 2; m = 5; p = 6; X = H; Y = NH-NH ;. Z = C00H (IBI-P-01062) . Into a solution of the compound of Example 20(27.5 g),in ethyl acetate (400 ml), cooled to 0°C, is bubbled gaseous HCl. The reaction mixture is stirred for 3 hours at room tem¬ perature , evaporated to dryness and taken up with deionized water (500 ml) and ethyl ether (300 ml). The phases are separated and the aqueous phase is evaporated to dryness. The thus obtained residue (13 g) is taken up with ethyl ether and stirred for 1 hour at -10°C. The reaction mixture is filtered, washing with a little cold ether. 5.8 g of the title compound is obtained. Analysis: m.p. = 118 -j- 120 °C I.R. (ύ ax) : 3300, 1600, 1550 cm "1 Elemental analysis : calculated found C 61.95 61.86 H 10.69 10.71 N 8.03 8.05 Examole 22 3-hexyl-(7-azido-heptyl)-cyclopentyl-azide SUBSTITUTE SΠLC The compound of Example 3 (20 g) rs handled as describe in Example 7 using CH Cl (120 ml), NζC^) (33.8 ml),mesyl chloride (16.4 ml), v/ater (190 ml) , ' NaN (14g), hexadecil- tributylphosphonium bromide (4.4 g) .After this reaction and chromatography, the title compound is obtained (18 g) . I.R. \) max) : 2200 cm " . Example 23 3-hexyl-2-(7-amino-heptyl)-cyclopentyl-amine . Derivative of formula (IA) wherein : n= 2; = 5; p = 6; X = H; Y = NH 2 ; Z = CH NH (IBI-P-01068) . The compound of Example 22 (18 g) is handled as de- scribed in Example 11, using MeOH (300 ml), ethyl ether(50 ml as co-solvent 5% Pd/C (7.2 g) . At the end of the reaction and after silica gel chroma¬ tography and elution with 8 : 2 methylene. chloride and meth¬ anol, 4.6 g of the title compound is obtained. Analysis: Titre as base = 90% I.R. ( ax): 3300, 1670 cm " Elemental analysis : calculated found c 76 . 6 76 . 5 H 13 .47 13 . 41 N 9 .93 9 .96 Example 24 3-hexyl-2-(6-carbomethoxy-hexyl )-cyclohexanone SUBSTITUTE i>πt » Into a suspension of Mg ( 4 .5 g) in anhydrous THE (130 ml) is added dropwise bromohexane (30.5 g) , refluxing the solvent until it is completely dissolved. The reaction mixture is cooled to 0°C , added with Cπl (3.5 g) and stirred for 1 hour at 0°C until the formation of alkyl-copper is ended. The mixture is then cooled to -30°C and added drop- wise, over 10 minutes, with a solution of 2-(carbomethoxy- hexyl)-2-cyclohexene-l-one (21 g) dissolved in THF (30 ml). After 15 minutes at -30 ÷ -25°C, a saturated solution of NH Cl in water, with pH adjusted to 8 with NH OH (300 ml) is added t rapidly. The reaction mixture is stirred from 30 minutes to 1 hour, at room temperature, and the phases are separated. The organic phase is washed to neutrality with a saturated sodium chloride solution and anhydrated. The solvent is then evaporated and chromatographed on silica gel, elu ing with 8 : 2 n-hexane/ethyl acetate, thus obtain¬ ing the "itle compound (18 g). I.R. ( max): 1740, 1710 cm " . Example 25 3-hexyl-2-(6-carboxy-hexyl)-cyclohexanone The compound of Example 24 (18 g) is dissolved in methanol (20 ml) and t.-eated with an NaOH (4g) solution in water (80 ml) . The reaction mixture is refluxed, under stirring, for 2 hours, it is cooled and acidified to pH 2, it is extracted with methylene chloride (80 ml) and washed with water to neutrality. The solvent is then anhydrated and evaporated. 15.5 g of the title compound is obtained. I.R. : 3300, 1740, 1710 cm ~~ suBSTi U e ^r.— Example 26 3-hexyl-2-(6-carboxy-hexyl )-cyclohexyl-amine. Derivative of formula (IA) wherein n = 3; m = 5; p = 6;- X = H; Y= NH ; Z = COOH (I3I-P-05006) . The compound of Example 25 is treated in an auto- cla e at 40 f 50°C with methanol (200 ml), ammonia . (35 g) , PtO (0.150 g) and kept under hydrogen pressure ( 5.7 atm) for 3 days. Thereafter, 9.9 g of the title compound is obtained. Analysis : I.R.( max) ' : 3300,1550 cm " ; m.p. = 161 163 °C Elemental analysis : calculated • found C 73.31 73.15 H 12.54 12.29 N 4.5 4.62 Titre as base = 97%. Example 27 3-hexyl-2-(7-amino-heptyl)-cyclohexyl-amine. Derivative of formula (IA) wherein n = 3; m = 5; p = 6; X = H; Y = NH ; Z = CH NH (IBI-P-05012) . This compound is prepared starting from 3-hexyl- 2-(6-carboxy-hexyl)-cyclohexanone of Example 25 with a process analogous to that used for preparing the compound IBI-P-01068 (Examples 22 and 23). Analysis : I.R. ( max) : 3280, 1460 cm " Tifere as base = 91%. ExamDle 28 3 - h exyl-2-(5-car b omethoxy-pentyl ) -cyclohexanone SUBSTlTUϊ g, Ϊ3»ι »— — 37 g of 2-(5-carbomethoxy-pentyl)-2-cyclo- hexene-1-one is handled as described in Example 24 using: bromohexane (54.5 g) Mg (7.92 g) THF (540 ml), Cul (12.3 g) , a saturated NH Cl solution at pH 8.4 (550 ml).At the end of. the reaction and after chromatography on silica gel, 38.4 g of the title compound is obtained. Analysis: I.R. ( - max) : 1740,1710 cm " L H-NMR: 3.7 (s, 3H) ; 2.3 (t, 2H) ; 1.4 f 0.9 (broad,29H) . Example 29 3-hexyl-2-(5-carboxy-pentyl)-cyclohexanone The compound of example 28 (20 g) is handled as described in Example 25, using methanol (25 ml), NaOH (5.1 g) , water (52 ml). Thereafter 18.1 g of the title com¬ pound. I.R. (0 max) : 3400 •=• 3700, 1700 cm "1 . Example 30 3-hexyl-2-(5-carboxy-pentyl)-cyclohexyl-amine. Derivative of formula (IA) wherein : n = 3; m = 5; p = 5; X = H; Y = NH ; Z = COOH (I3I-P-05008) . The compound of Example 29 (18.1 g) is treated in an autoclave,at room temperature, together with methanol (200 ml), ammonia (62 g) ,Pt0 (0.18 g) and left under hydrogen pressure for 3 days. At the end of which and after crystallization from ethyl ether (100 ml) 12 g of the title compound is obtained. Analysis ' : I.R. (- ' } max) : 3400 2800, 1550 cm "1 m.p. : 155 158 °C, with decomposition Titre as base = 98 %c Elemental analysis: calculated found C 72.67 72.42 H 11.86 11.68 N 4.70 4.59 Example 31 3-hexyl-2-(6-cyano-hexyl)-cyclohexyl-amine.Derivative of formula (IA) wherein : n = 3, m = 5; p = 6; X = H; Y = NH ; Z = CN (I3I-P-05009) . This compound is prepared starting from 3-hexyi- 2-(6-carboxy-hexyl)-cyclohexane of Example 25, by an analo¬ gous process to that used for the preparation of the compound IBI-P-01037 (Examples 3,4,5,6,7,8). Analysis: _ι I.R. ( O max) : 2220 cm 1 H-NMR: 2.2 (t, 2H) ; 1.4 (s, 2H) ; 1.2 - 0.9 (broad,31H) Titre as base = 92 Elemental analysis calculated found C 78.41 78.32 H 12.47 12.45 N 9.62 9.63 Example 32 5-spiro-/_2-(7-carboxy-hexyl)-3-hexyl-cyclohexyl_/-imidazoline- 2,4-dione. Derivative of formula (IA) wherein : n = 3; = 5; p = 6; X and Y, taken together, form a hydantoin nucleus; • Z = C00H ( I3I-P-05010 ) . The compound of Example 25 (13 g) is dissolved in an NaOH solution (2.32 g) in water (90 ml) and handled as described in Example 2, using KCN (3.8 g) ~ , (NH ) CO (17 g) , water (90 ml) . Whereupon the title compound is obtained as a white crystalline solid (12.5 g) . Analysis: _1 I.R. ( max) : 3250, 1720, 1630 cm k-NMR : 8.3 (s, 1H) ; 2.36 (t, 2H),1.8 -_ ■ 0.9 (broad 33H) Titre (acid) = 97% Elemental analysis : calculated found c 66.28 65.75 H 9.53 9.73 N 7.35 7.25 Example 33 3-hexyl-2-(6-carbomethoxy-hexyl)-carbonyl-cyclohexane A solution of potassium ter.butylate (14.5 g) in DMSO (1.5 1 ) is added, under argon, with Ph PC1CH OMe (44.4 g) and, after 20 minutes, with the compound (28g) of Ex¬ ample 24, stirring for 16 hours.The reaction mixture is then poured into cold water (500 ml) and acidified with 6N HCl (30 ml), extracted with ethyl ether (500 ml) and washed up to neutrality with a 1:1 water/saturated NaCl solution. The solvent is anhydrated and evaporated to dryness, under re¬ duced pressure, chromatographed on silica gel and eluted with 8 : 2 hexane/ethyl acetate, thus obtaining 23 g of a yellow oil which Is taken up with acetone (500 ml) and 3N HCl (120 ml) and stirred for 1 hour. It is then diluted with -- - water (300 ml) and extracted with ethyl ether (3CC ml). The e t heral phase is washed with a 1:1 water/saturated :iaCl solu¬ tion up to neutrality and anhydrated. The reaction mixture is evaporated under reduced pressure yielding 21 g of the title compound. I.R. (>> max.): 2720 , 1740 cm " Exarmole 34 3-hexyl-2-(6-carbomethoxy-hexyl)-hydroxymethyl-cyclohexane The compound of Example 33 (21 g) is dissolved in MeOH (200 ml) and treated, portionwise, with Na3H (1.12 g) at 0° ÷+5°C. After 1 hour at 0° +5°C, the reaction mixture is slowly acidified with 3N HOI and the phases are extracted with ether (300 ml). The ethereal phase is washed with water up to neutrality an anhydrated. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel, eluting with 8 : 2 hexane/ethyl acetate, thus obtaining 8 g of the title compound. I.R. (\) max.): 3200 cm " , 1740 cm " . Examole 35 3-hexyl-2-(6-carbomethoxy-hexyl)-azidomethyl-cyclohexane The compound of Example 34 (8 g) is treated as described in Example 7, using CH Cl (100 ml),N(C H ) 2 2 2 5 3 (4.95 ml), mesyl chloride (2.4 ml), NaN (38 g) , water (50 ml) ,hexadecyl-tributylphosphonium bromide(1.2 g) .where¬ upon 8.6 g of the title product is obtained. Elemental analysis : calculated found c 69.00 • 66.91 H 10.75 10.53 N 11.40 11.24 Example 36 3-hexyl-2(6-carboxy-hexyl)-aminomethyl-cyclohexane. Deriva- tive of formula (IA) wherein : n = 3; m = 5; p = 6; X = H; Y = CH NH ' ; Z = C00H (IBI-P-05011) . The compound of Example 35 (8.3 g) is handled as described in Example 8, using methanol (160 ml), 5% Pd/C (1.1 g) , whereafter a clear oil (7.4 g) is obtained which is taken up with methanol (25 g) and added to a solution of NaOH (1.49 g) In water (50 ml). The reaction mixture is heated at 65°C for 2 hours, under stirring, it is then cooled to room temperature and " the pH is adjusted to 5.5 with 6N HCl. The reaction mixture is then stirred for 1 hour at +5°C, the solid thus obtained is filtered and washed first with a small amount of cold methanol and then with ether.It is. filtered • and dried under reduced pressure yielding 3.5 g of the title compound. Elemental analysis: calculateid found C 73.79 73.78 H 12.07 12.14 N 4.3 4.39 Titre as base = 94% Example 37 2-pentyl-3-(7-carboxy-heptyl)-cyclopentanol SUBSTITUTE nttr A solution of 2-(n-pentyl)-3-(carbomethoxy heptyl) cyclopentane-1-one (150 g) (prapared in like manner as de¬ scribed in IL FARMACO 27_, 610 (1972)), in methanol (800 ml), is treated, portionwise, with Na3H (24.1 g) at 0 +5°C. After 1.5 hours at 0 7 +5°C, the reaction mixture is poured into water (900 ml.), acidified with 6N HCl and extracted with ethyl ether (1 1 ) .The organic phase is washed with water to neutrality and anhydrated. The solvent is evaporated and 148 g of a clear oil is obtained. _1 I.R.(\) max) : 3200, 1735 cm Example 38 2-pentyl-3-(7-carboxy-heptyl)-cyclopentyl a ine.Derivative of formula (IB) wherein : n = 2; m = 4; p = 7; X = H; Y = NH ; Z = COOH (I3I-P-10002) . The compound of Example 37 (148 g) is handled, as described in Examole 7, using CH_C1_ (1.5 It), (C_H_)_ -d -d -d b 3 (109 ml), mesylchloride (54.8 ml) NaN (64.5 g) , water (1.3 1 ), hexadecyl-tributylphosphonlum bromide (23.5 g) , whereupon 143 g of chromatographed compound (I.R.=2100 cm ) is obtained which is treated as described in Example 8,using methanol (1.5 It), 5% Pd/C (24 g). 100 g of a clear oil is obtained which is treated as described in Example 19, using methanol (700 ml), K 2 C0 (93 g) , water (310 ml). Thus 48 g of the title compound is obtained in the form of a white crystalline solid. Ξlemental analysis calculate:d found C 72.67 72.58 H 11.86 11.83 N " 4.71 4.82 - ' 5 Example 39 N-/_2-p ntyl-3-(7-carboxy-heptyl)-cyclopentyl/-methyl-amine. Derivative of formula (IB) wherein : n = 2; m = 4; p = 7; X = H; Y = NHCH ; Z = C00H (IBI-P-10004) . A solution of 2-(pentyl-3-(caboxy-heptyl)-cyclo- 10 pentane-1-one (50 g) in methanol (100 ml) is added with a solution of -NaOH (6.9 g) in methanol (100 ml). Said solution is treated in a 500 ml steel autoclave with CH NH (53 ml) and PtO (1 g) at -40°C. It is left under hydroge (4 a tm.)an d heated at ' 50°C for 24 hours. The catalyst is then filtered 15 off and desiccated,yielding 50.8 g of a semi-solid white compound. This residue is taken up with CH CN (700 ml) for 3 hours at 0 ÷- +5°C, filtered off, yielding 50 g of the title compound in the form of a white crystalline solid. Analysis: -20 m.p. : 200 f 224 °C. Titre as base = I.R. (^ max): 3300, 1500 cm " i-NMR: 8.1 (s, 1H) ; 2.5 (s, 1H) ; 1.8 τ 0.9 (broad, 32 H) . Example 40 25 2-pentyl-3-(8-hydroxy-octyl)-cyclopentyl amine. Derivative of formula (IB) wherein : n = 2; m = 4; p = 7; X = H; Y = NH ; Z = CH OH (IBI-P-10007) . The methyl ester of the compound of Example 38 is handled a s described in Example 1, using ethyl ether (300 ml), 30 LiAlH (2.85 g) , whereupon 16.8 of the title compound is obtained. SUBSTITUTE π Analysis : Titre as base = 96% I.R. (0 max) : 3000, 1550 , 1460 cm " 1 H-NMR i 3.6 (t, 2H) ; 2.4 (s, 3 Examole 41 2-(6-carboxy-hexyl)-3-heptyl-cyclopentyl amine. Derivative of formula (IA) wherein: n = 2. m = 6; p = 5; X = H; Y = NH ; Z = C00H (I3I-P-12004) . This derivative is prepared starting from 2-(carbo- methoxy-hexyl)-cyclopentyl-2-ene-l-one by an analogous method to that used for preparing the compound I3I-P-10002 (Examples 37 and 38). Analysis: I.R. ( max) : 3300, 1560 cm " Titre as base = 94% Elemental analysis: calculated found C 68.43 67.8 H 10.88 10.51 N 4.20 4.09 Example 42 2-(6,6-diethoxy-hexyl)-3-hexyl-cyclopentyl amine.Derivative of formula (IA) wherein n = 2; m = 5; p = 5; X = H; Y = NH ; Z = CH(OEt) (IBI-P-12007) . This compound is prepared starting from 2-(5-car- bornethoxy-pentyl)-cyclopent-2-ene-l-one by an analogous method to that used for preparing the compound I3I-P-01053 (Examples 9,10 and 11). Analysis : I.R. (0 max) : 3340 cm 1 H-NMR : 4.6 (t, 2H); 3.6 (m, 5H) ; 2 (s,2H); 1.9 ÷ 0.9 (broad, 30H) . *"—- Titre as base = 96% Elemental analysis : calculated found c 73.84 73.69 H 12.69 12.58 N 4.09 4.20 Example 43 2-( 6 , 6-diethoxy-hexyl ) -3-heptyl-cyclopentyl amine . Deriva- tive of formula (IA) wherein : n = 2 ; m = 6 ; p = 5 ; X = H ; Y = NH„ ; Z =-CH(0C„H_ ) . ( IBI-P-12008 ) . 2 2 b This derivative is prepared starting from 2-(5-car- bomethoxy-pentyl)-cyclopent-2-ene-l-one by an analogous method to that used for preparing the compound IBI-P-01053 (Examples 9,10 and 11) . Analysis: -1 I.R. ( ^max) : 3350 cm H-NMR 4.4 (t,lH); 3.5 (m, 5H) ; 1.4÷0.9 (broad, 37H) Titre as base = 95 Example 44 5-spiro /_2-(5-carboxy-pentyl)-3-heptyl-cyclopentyl/-imida- zoline-2,4-dione.Derivative of formula (IA) wherein: n = 2; = 6; p = 5; X and Y constitute the hydantoin nucleus; Z = C00H (IBI-P-12009) . This compound is prepared starting from 2-(5-carbo- methoxy-pentyl)-cyclopent-2-ene-l-one by an analogous process as that used for preparing the compound IBI-P-01028 (Ex. 2) . Analysis : -1 I.R.(\) max) 3700, 3100, 1770, 1740, 1720, 1460 cm 1 H-NMR : 9.5 (s, 1H) 7.3 (s, 1H) ; 2.3 (m, 4H) ; 1.440.95 (broad, 27H) . SUBSTITUTE Shtfc Example 45 l-cyano-2-(6-carbomethoxy-hexyl)-3-hexyl-cyclopentyl amine A solution of NaOH (4.55 g) in water (100 ml) is added, portionwise, with 9-oxo-19,20-bis-nor-prostanoic acid and Teft under stirring until it is completely dissolved. 1Q 30% NH OH (150 ml), NH Cl (10.1 g) and KCN (12.28 g) are then added at room temperature. The reaction mixture is stirred for 3 days at room temperature. It is then cooled to 0°C and cautiously acidified with concentrated hydrochloric acid so as to adjust the pH value at 4, and extracted with ethyl ether ις (500 ml). The ethereal extract is washed with water and an¬ hydrated. Upon evaporation of the solvent under reduced pres¬ sure, a brown oil (29 g) is obtained which is taken up with methanol (300 ml), p-toluene-sulfonic acid (18.5 g) and the solution is refluxed for 2 hours. Whereupon the solvent is ■ 20 evaporated to small volume, poured into water (300 ml) and 10% NaOH (10 ml) and extracted with ethyl ether (300 ml). The etheral extract is washed with water to neutrality and anhydrated. After evaporation and silica gel chromatography, 25 eluting with 7 : 3 hexane/ethyl acetate, 12 g of the title compound is obtained. Analysis : I.R. ax)_ : 3320, 3350, 2220, 1740, 1620 cm "1 Titre as base = 98% 30 SUBSTITUTE Sέπt » Examp le 46 l-aminomethyl-2-(7-hydroxy-heptyl)-3-hexyl-cyclopentyI amine. Derivative of formula (IA) wherein : n = 2; m = 5; p = 6; X = NH ; Y =CH NH " ; Z = CH OH (I3I-P-01070) . ' To a suspension of LiAlH (3.42 g) in THF (90 ml), heated to reflux, is added dropwise a solution of compound of Example.45 (10 g) dissolved in THF (20 ml). The solution is refluxed for 2V Z hours and cooled to 0°C. Water (20 ml) and ethyl ether (100 ml) are then cauti-ously added dropwise.The phases are separated and the aqueous phase is extracted with ethyl ether (100 ml). The etheral phases are washed with water to neutrality and anhydrated. After evapora¬ tion and silica gel chromatography, eluting with 7 : 3 methyl¬ ene chloride/methanol, the title product is obtained (3.5 g) . Analysis : I.R. ($ max) : 3300, 1650, 1480 cm "1 " Sl-NMR : 3.6 (t, 2H) ; 2.5 (s, 2H) ; 2.1 (s, 5H) ; 1.7-0.9 (broad, 31H). Titre as base = 98%. SUBSTITUTEbπ - •

Claims: C L A I M S 1 . A compound of formula including the possible optical and/or geometric isomers wherein: n = 2, 3; m = 4, 5, 6, 7; p = 5, 6, 7; Υ, when X=K, -NK , represents -NH-NH , -CH NH , -NRR*, wherein R and R' may be the same or different, each representing: H, a linear or branched alkyl, alkenyl, alkynyl, phenyl, substituted aryl, or, taken together with the substituent X, it may con¬ stitute the hydantoin nucleus : and Z = -CN, -CH NH -COCK. .CH. -c cow, OR OR' wherein R and R" have the meanings given above and W may be -OR, -NRR' , except for those compounds corresponding to the formula (IA) wherein: n = 2; m = 5, p = 6; X = H; Y = NRR 1 ; and Z = C-Q II o wherein Q = -OH, (C -C )-alko ' xy, phenoxy, butyloxy, or -NHR", wherein R" is (C -C )alkyl or H. 2. A compound of formula ( ^ UBSTITUTE s s c & inc l u d ing t h e possible optical and/or geometric Isomers where ¬ in: n = 2,3; m = 4,5,6,7; p = 5,6,7; Y, when X = H,-NH 2 , re ¬ presents -NH-NH 2 , -CH 2 NH 2 , -NRR', wherein R and R' may be the same or d ifferent, each representing : H, a linear or branched alkyl, alkenyl, alkynyl, phenyl, su b¬ stitute d aryl or, taken together with the substitutent X, it may constitute the hydantoin nucleus, and CH Z wherein R and R' have the meanings given above and W may be -OR, -NRR' . 3. A compound according to claim 1, wherein n = 2, m = 5, p = 6, Y =-NH , X = H and Z =-CH OH. 4. A compound according to claim 1, wherein: n = 2, m = 5, p = 6, Y and X, taken together, constitute the h dantoin nucleus and Z = -COOK. 5. A. compound according to claim 1, wherein: n = 2, m. = 5, p = 6, Y = -NH , X = H and Z = -CN. 6. A compound according to claim 1, wherein: n = 2, m = 5, p = 6, Y = -NH., X = H and Z=-CH(0C o H c ) n 2 5 2 7. A compound according to claim 1, wherein: n = 2, m = 5-, p = 6, Y =-NH , X = H and Z=-C(0C H ) CH . 8. A compound according to claim 1, wherein: n = 2, m = 5, p = 6, Y = -CH NH , X = H and Z = -C00H. 9 ' A compound according to claim 1, wherein: n = 2, m = 5, p = 6, Y = -NHNH 2> X = H and Z = -C00H. 10. A compound according to claim 1, wherein: n = 2, m = 5, p = 6, Y = -NH 2> X = H and Z = -CH NH . 11. A compound according to claim 1, wherein: n = 3, m = 5, p = 6, Y = -NH ? , X = H and Z = -C0OH. SUBSTITUTESnt.*- 12. A compound according to claim 1, wherein: n = 3, m = 5, p = 5, Y = -NH , X = H and Z = -C00H. 13. A compound according to claim 1, wherein: n = 3, m = 5, p = 6, Y = -NH , X = H and Z = -CN. 14. A compound according to claim 1, wherein: n = 3, m = 5, p = 6, Y and X, taken together, constitute the hydantoin nucleus and Z = -C00H. 15. A compound according to claim 1, wherein: n = 3, m = 5, p = 6, Y = -CH NH , X = H and Z = -COOH. 16. A compound according to claim 1, wherein: n = 3, m = 5, p = 6, Y = -NHg, X = H and Z = -CH NH ? . 17. A compound according to claim 1, wherein: n = 2, m = 6, p = 6, X = H, Y =→TH . and Z = COOH. 18. A compound according to claj.m 1, wherein: n = 2, m = 5, p = 5, Y = -NH , X = H and Z = -CH(0C H ) . 19. A compound according to claim 1, wherein: n = 2, m = 6, p = 5, Y = -NH g , X = H and Z = -CH(0C H ) . 20. A compound according to claim 1, wherein: n = 2, m = 6, p = 5, Y and X, taken together, constitute the hydantoin nucleus and Z = -COOH. 21. A compound according to claim 2, wherein: n = 2, m = 4, p = 7, Y = -NH , X = H and Z = -COOH. 22. A compound according to claim 2, wherein: n = 2, m = 4, p = 7, Y = -NHCH , X = H and Z = -COOH. 23. A compound according to claim 2, wherein: n = 2, m = 4, p = 7, Y = -NH , X = H and Z = CH OH. 24. A compound according to claim 1, wherein: n = 2, m = 5, p = 6, Y = -CH NH , X = NH and Z =-CH OH. 25. A process for preparing a compound of formula (IA) according to claim 1, wherein X is H and Y is SUBSTITUTES ctι the -NRR" group,wherein R and R' can be the same or d ifferent, each representing H, a linear or branched alkyl, alkenyl, al k ynyl, p h enyl or su b stituted aryl, characterized b y t h e fact that a cyclic k etoπe of formula (IIIA), wherein the letters n, , p, Z have the meanings indicated in formula (IA), is ma d e to react with ammonia or with an -NHRR' amine, in a polar organic solvent, under hydrogen atmosphere and in the presence of a metal catalyst, at a temperature rang- ing from 20°C to the reflux temperature of the reaction mix¬ ture, over a period of time from 1 to 100 hours. 26. A process for preparing a compound of formula (13) according to claim 2, wherein X is H and Y is the -NRR 1 group, wherein R and R' can be the same or different, each representing H, a linear or branched alkyl,alkenyl, al- kynyl, phenyl or substituted aryl, characterized by the fact that a cyclic ketone of the formula (IIIB), wherein the let¬ ters n, m, p and Z have the meanings indicated in the formu¬ la (IB), is made to react with ammonia or an -NHRR' amine, in an organic polar solvent, under hydrogen atmosphere and in the presence of a metal catalyst, at a temperature rang¬ ing from 20°C to the reflux temperature of the reaction mix¬ ture, over a period of time of from 1 to 100 hours; 27. A process for preparing a compound of formula (IA) according to claim 1, wherein X and Y,taken together, constitute the hydantoin nucleus, characterized by the fact that a ketone of formula (IIIA), wherein the letters n, m, p and Z have the meanings indicated in formula (IA), is made to react with an alkali or alkaline earth metal cyanide, under controlled pH, in a polar solvent and at a temperature of from 20°C to the reflux temperature of the reaction mix¬ ture, over a period of time of from 1 to 20 hours. SUBSTITUTE n *» " 28. A process for preparing a compound of formula (IB) according to claim 2, wherein X and Y, taken together, constitute the hydantoin nucleus, characterized by the fact that a ketone of formula (IIIB) ,wherein the letters n, m, p and Z have the meanings indicated in formula (IB), is made to react with an alkali or alkaline earth metal cyanide, under controlled pH, in a polar solvent and at a temperature of from 20°C to the reflux temperature of the reaction mix¬ ture, for a period of time of from 1 to 20 hours. 29. A pharmaceutical composition having anti-ulcer activity characterized by the fact that it contains, as the active ingredient, a compound of formula (IA) according to claim 1, or a pharmaceutically acceptable salt thereof. 30. A pharmaceutical composition having anti-ulcer activity characterized by the fact that it contains, as the active ingredient, a compound of formula (IB) according to claim 2, or a pharmaceutically acceptable salt thereof. SUBSTITUTE SHtE *

Inventors: VALCAVI UMBERTO, VALCAVI, UMBERTO
Applicants: ISTITUTO BIOCHIMICO ITALIANO, IBI ISTITUTO BIOCHIMICO ITALIANO GIOVANNI LORENZIN
Application year: 1988
Main classification: C07C177
IPC codes: C07C35, C07C45, C07C47, C07C405, C07D235