USOO621.1233B1 (12) United States Patent (10) Patent No.: US 6,211,233 B1 Del Soldato (45) Date of Patent: Apr. 3, 2001

(54) PROSTAGLANDIN PHARMACEUTICAL FOREIGN PATENT DOCUMENTS COMPOSITIONS 0.357581 3/1990 (EP). 92/01668 6/1992 (WO). (75) Inventor: Piero Del Soldato, Milan (IT) 94 06433 3/1994 (WO). 94 101.41 5/1994 (WO). (73) Assignee: Nicox S.A., Paris (FR) 9530641 11/1995 (WO). (*) Notice: Subject to any disclaimer, the term of this 95/30641 11/1995 (WO). patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 0 days. Hempelmann et al., “Non-Synergistic relaxant effects of (21) Appl. No.: 09/423,286 vasoactive intestinal polypeptide and SIN-1 in human iso (22) PCT Filed: Jun. 17, 1998 lated cavernous artery and corpus cavernoSum' European Journal of Pharmacology, vol. 276, 1995, pp. 277–280. (86) PCT No.: PCT/EP98/03645 Duarte et al., “Peripheral analgesia and activation of the S371 Date: Nov. 8, 1999 nitric oxide-cyclic GMP pathway” European Journal of S 102(e) Date: Nov. 8, 1999 Pharmacology, vol. 186, 1990, pp. 289-293. Stack et al., “Intracavernous Injection of Vasoactive Drugs (87) PCT Pub. No.: WO98/58910 in the Rabbit" Urological Research vol. 16, 455-458. PCT Pub. Date: Dec. 30, 1998 Martinez-Pineiro et al., “Cyclic Guanosine Monophosphate Mediates Penile Erection in the Rat Research Paper Eur (30) Foreign Application Priority Data Urol, 1993, vol. 24, 492-499. Jun. 19, 1997 (IT) ...... MI97AOO1440 (51) Int. Cl." ...... A61K31/21; CO7C 203/04 Primary Examiner Bernard Dentz (52) U.S. Cl...... 514/509; 514/468; 549/462; (74) Attorney, Agent, or Firm-Arent, Fox, Kintner, Plotkin 558/480; 558/482; 558/483; 558/484 & Kahn (58) Field of Search ...... 549/462; 558/480, (57) ABSTRACT 558/.482, 483, 484; 514/509,468 Compounds of the general formula A-X-NO, or their (56) References Cited pharmaceutical compositions, wherein A contains a proStag landin residue, X is a bivalent connecting bridge. U.S. PATENT DOCUMENTS 5,625,083 4/1997 Bezuglov et al...... 560/121 6 Claims, No Drawings US 6,211,233 B1 1 2 PROSTAGLANDIN PHARMACEUTICAL R is a radical having the following formula: COMPOSITIONS (III) This application is a 371 of PCT/EP98/03645 filed Jun. 17, 1998. R25 Rs R13 The present invention relates to drugs to be used in male B R R19 | R15 impotence. in----C6 C 1 In particular it relates to drugs which are used at lower R26 R 6 R14 but equally effective doses than those commonly used for the R4 R20 R16 treatment of Said therapy, and combined with fewer side effects, in particular as far as the absence of hypotension and R17 R23 algogenic activity is concerned. OH 1. 's 16 It is well known in the art that the available therapies for R10 R12 C17 treating male impotence are based on different approaches depending on the aetiology. 15 In the case of impotence due to endocrine causes treat ment with testosterone is used. In the case of impotence due to vascular alterations, or where mo is an integer and can have a value of 0 or 1; following from Some neurological alterations, it is used an where the meaning of the various Substituents of formula intracavernous injection of vasoactive compounds made by III is as follows: the patient himself before sexual intercourse. This method of when t=1, u=0 and mo=1; administration allows a local pharmacological activity and R=H; an alkyl having from 1 to 6 carbon atoms, pref reduces to a minimum any interference with the other vascular areas of the body which could lead to severe side erably from 1 to 3, or a free valence; effects including vasodilation and hypotension. The drugs 25 R=OH; O- such as to form with R, when R is a free more frequently used with Said method include the associa Valence, and with the carbon atom at position 15, a tion papaverine-phentolamine and Prostaglandin E. (PGE). group C=O, This is a useful approach from the therapeutic point of view, R, R, equal or different one from the other, are equal to but it has the disadvantage to presenting Side effects. In fact, R, or one of them is a bond O-, and the other is a free papaverine induces local fibrosis, prolonged erections and Valence So that with the carbon atom C they form a hepatic alterations; Prostaglandin E induces pain in 20% of group C=O; cases and prolonged erections in 1-2% of cases. PGE is anyhow at the moment the drug most used for this type of Rs, R, equal or different one from the other, are equal to therapy. R, in particular when both Rs and R are each a free Besides clinical drug treatments, are well known in the 35 Valence, Rs and R form a double bond between Cs and art the use of prostheses and mechanical devices. Co.; At the present time, the available drugs Solve the problem R7, Rs, Ro, Rio, equal or different one from the other, have only in a limited number of cases. Research is being made the same meaning of R, when R, or Ro, and at the on the basis of various hypothesis. However, the drugs Same time Rs or Ro are each a free Valence, there is a which have been proposed up to now are less active than 40 double bond between C and C, prostaglandin-based drugs. It was felt the need to have drugs as effective in the treatment of impotence as least as those based on prostag R=R or OH; landin but without presenting the Side effects possessed by R. R., Ris, R, equal or different one from the other, Said known drugs as described above. 45 are equal to R; when R or Rs, and at the Same time It has been Surprisingly and unexpectedly found a class R or R, are each a free Valence, there is a double of drugs as herein below defined which has an improved bond between C and C, activity than prostaglandin and the advantage of being used R7, Ris, equal or different one from the other, are equal at lower doses with leSS Side effects, in particular it does not to R; cause any hypotension or algogenic activity. 50 It is an object of the invention the compounds, or their Rio, Rao, equal or different one from the other, are equal compositions having the general formula to R; when R or Rs is a free Valence, and at the same time Rio or Rao is a free Valence, there is a double bond between C and Cs; A-X-NO, (I) 55 R2, R22, R2, R2, equal or different one from the other, for use as medicaments, in particular as drugs for the are equal to R; treatment of impotence, wherein: Rs, R, equal or different one from the other, are equal to R, but both Rs and R2 cannot be a free Valence; R27 is a linear or whenever possible branched alkyl A=R(CRRO)(COX), (II) 60 having from one to six carbon atoms, wherein: B is equal to the group O= (a keto group with the carbon t and u are integers and are equal to 0 or 1, atom at position 9 of the prostaglandin molecule), OH X=O, NH, NR wherein R is a linear or branched alkyl or -O-, having from 1 to 10 carbon atoms, 65 when no aliphatic chain C7-C is found attached at R, and R, equal or different from each other, are H, position 8, in its place there is the alkylaromatic resi C-C alkyl, due: US 6,211,233 B1 4 where nf is an integer from 1 to 6, preferably from 2 to 4; (IV) -(CH-CH-O)- o cul-O) where R=H, CHs and nf is an integer from 1 to 6, wich is bound to formula (III) (B=-O-) in the following preferably from 2 to 4. way: When in formula (II) t-1 u=0 and in formula (III) mo-1, the preferred prostaglandin residues R are the following: (V) when B is O= (keto group with Co.); R7, Rs, Ro and Rio are Such as to give a double bond between C and C, o (CRaRb)n 1 R is OH; R, is CH; the substituents of the carbon atoms of the C-C, and Co-Co aliphatic chains are H, 15 R thus defined is known as the residue of Prostaglandin E1, or, by putting in the formula of Prostaglandin E. R=CH and R, R, Rs, R. Such as to give a double bond between Cs and C, wherein m is an integer from 1 to 6, preferably from 1 to R thus defined it is known as the residue of Arbaprostil; 3; or, by putting in the formula of Arbaprostill R-7=Ro=Ro= R, and R, equal or different from each other, are as above Ro=H; R and R are Such as to form the group C=O defined; with Cs; B is OH; R,-CHz, R thus defined it is when t=0, u=1 and mo=1 the meanings of the various 25 known as the residue of Unoprostone; Substituents are as above defined; or, by putting in the formula of Arbaprostill R=R=CH, when t=0, u=0 and mo=0 the meanings of the various R=H, R thus defined it is known as the residue of Substituents are as above defined and Trimoprostil; C is bound, optionally by a bridging group -O-, to an or, when in the formula of Arbaprostill B is OH; R = H, R aromatic radical or an alkyl-aril radical, where the aryl thus defined it is known as the residue of Prostaglandin can be Substituted, preferably with halogens, preferably F2. with Cl, F. Said aryl radical can also contain or, when in the formula of Prostaglandin R B is O= heteroatoms, such as O, N, the alkyl of the alkyl-aril (keto group with Co), R thus defined it is known as the radical is an aliphatic chain from 1 to 3 carbon atoms, residue of Prostaglandin E, preferably -CH-, 35 or, when in the formula of Arbaprostill B is OH; R thus X of formula A-X-NO is a bivalent connecting defined it is known as the residue of Carboprost; bridge, chosen from the following: or, by putting in the formula of Arbaprostill R=H; R =H; Ro=CH, R=R=Rs=Re=H; R7–CHS, R=Re=H and R=Rs being free Valences Such as to form a 40 double bond between C2 and C3; R thus defined it is known as the residue of Limaprost; or, by putting in the formula of Trimoprostill R=R=Rs= Y is a linear or whenever possible branched C1-C20 Re=H and positioning the double bond between C and alkylene oxygen terminated, preferably having from 2 C instead that between Cs and C R thus defined it is to 5 carbon atoms or is a C5-C7 cycloalkylene oxygen 45 known as the residue of Gemeprost, terminated optionally Substituted; or, by putting in the formula of Arbaprostill R=R=H; R=OH; R =CH; R=Rs=R=R=H; R thus defined it is known as the residue of Misoprost; 50 or, by putting in the formula of Arbaprostill R=H; R = CH, R7–CHs; R and R are Such that one of them - (CH), is a free Valence and the other is a single bond with an Oxygen atom So So that together with the carbon atom C. they form a keto group C=O; R5=R6=H; R thus where n is an integer from 0 to 3, defined it is known as the residue of Ornoprostil; 55 or, as in Arbaprostil, without the C7-Caliphatic chain CHO and the carbon atoms Co-Cs being linked to the group of formula (IV) as shown in (V); R =H; R =CH; R, R, R2 and R being each a free Valence So to form yS-X 60 a triple bond between Cs and Co.; R thus defined it is COOH CH known as the residue of Beraprost; o (CH2- CH- CH- O)f- when t=0; u=1 and mo-1: R=R=H and R is the residue of Misoprostol; R thus defined it is known as the (CH-CH-CH-O)- ONO residue of Rioprostil; ONO2 65 when t=1, u=0 and mo-0: when R is the residue of Arbaprostill except that R=H, Rio or Rao is a free Valence or is H, So that between C. US 6,211,233 B1 S and Cs there is a double bond; C is linked to a group -O-A, wherein A=phenyl; R thus defined it is where X=YO. known as the residue of Enprostil, In the case of amides, the Synthetic Sequence includes when R is the residue of Arbaprostill except that B is OH; reaction of the same acyl chlorides RCOCl with aminoal R=H, C is linked to a group -CH2-A, where A is cohols of the general formula: phenyl; it is defined a radical known as the residue of Latanaprost; or, when in the formula of Enprostill Ro-Ro-H; it is defined a radical known as the residue of Sulprostone. to give amides of the general formula: The products of the invention are obtained Starting from the precursors in which R is as above defined and containing at least one carboxylic function, usually at position 2 of the R-CO-NH-Y-OH and R-CO-NR-Y-OH corresponding formula (III); in the case of Beraprost the function -COOH is in the residue of formula (IV). according to known methods. When the precursor has no free function -COOH, reac 15 The reaction of these amides with halogenating agents tions to obtain it which are well known in the art are Such as, for example, PCls, PBr, SOCl, and others, leads performed, for example by reaction of an esther or by to halogen derivatives of the general formula: oxidation of an alcohol. The above Substances may already exist as Such (e.g. Arbaprostil, Prostaglandin E, Rioprostil, as described R-CO-NH-Y-Br(CI) and R-CO-NR-Y-Br(Cl). above). By reaction with AgNO in acetonitrile according to For the precursors described in the literature, which have methods reported in the literature, are obtained the final the carboxylic function Substituted in various ways, in order products A-X-NO. to perform the Synthesis according to the present invention The Sequence of the reaction can be Schematised as it is preferable to Start from the corresponding precursors in 25 follows: the acid form, i.e. bearing e free carboxylic group. In particular, as preferred precursors one may mention Prostaglandin E, Arbaprostil, Unoprostone, Trimoprostil, R-CO-CI+ NHR-Y-OH----> Prostaglandin F, Prostaglandin E, Carboprost, Limaprost, PCls Misoprostol, Ge meprost, Latanoprost, Ornoprostil, R-CO-NRY-OH----> R-CO-NR-Y-Br+ Beraprost, Enprostil, Rioprostil, Sulpostrone. These sub AgNO3 ------R-CO-NR -Y-ONO stances are prepared according to the methods described in “The Merck Index’, Ed. 12, herein fully incorporated by reference. where YO is X. 35 An alternative route to formation of the esters is reaction The products of the present invention having the general of the Sodium or potassium Salts of the acids with the nitric formula esters of halogen alcohols of the general formula:

A-X-NO. 40 NO-O-Y-Cl(Br, I) with the connecting bridge X as above defined, are obtain able by using the methods of the known art described, for to directly give the products of the invention. example, in WO92/01668 and WO95/30641, herein fully The reaction scheme is as follows: incorporated by reference. In general, the connection between A and X is of the ester-C(O)O-type or amide 45 -C(O)NH- or -C(O)N(R)- type, as defined in X of formula (II) above, and can be obtained by using known where YO is X. Synthetic routes. According to a further proceSS for the preparation of the The most direct Synthetic route includes reaction of acyl compounds of the invention the acid derivatives RCOOH chlorides R-CO-Cl in halogen alcohols of the type 50 are reacted with alcohols containing in the molecule a group HO-Y-Cl, HO-Y-B, HO-Y-I, Y being X without -ONO in the presence of aromatic sulphochlorides, in the oxygen in experimental conditions which are part of the presence of bases, Such as trialkylamine, which neutralize known art. the HCl released by the reaction. The reaction products of formula R-CO-O-Y-Cl Can also be used Synthetic routes Similar to those (Br, I) can also be obtained by reaction of the sodium or 55 described above, where the di-halogen derivative BrY is potassium salts of said acids RCOOH with dihalogen deriva reacted with -ONa. The reaction products are then con tives of the general formula YCl, YBr or YI. verted into acetonitrile by reaction with AgNO, according to The reaction products are converted into the final products the above shown reactions. by reaction with AgNO, in acetonitrile, according to the The general Scheme is shown below known methods of literature. 60 The general Scheme is as follows: AgNO3 R-CO-Cl+HO-Y-Br->R-CO-O-Y-Br+ -ONa+ Bry -----> O-Y-Br ------O-Y-ONO AgNO->A-X, NO. where X=YO. In addition to being used in the treatment of male impo Another general Scheme is as follows: 65 tence as explained at the beginning, the product of the R-CO-ON a + Br, Y-> R-CO-O-Y-Br+ invention can also be used in the known therapeutic appli AgNO->A-XNO cations of drugs containing prostaglandins as the active US 6,211,233 B1 7 8 ingredient, Such as in the treatment of cerebrovascular and (-O-NO). 12.4 mg (65% of the starting amount) of cardiovascular disorders, glaucoma, peptic ulcer and as unreacted PGE was recovered from the chromatographic abortifacients. fractions eluted with the ethylacetate/methanol mixture. In particular, the derivatives of Prostaglandin E are preferred. Pharmacological tests Following treatment of experimental animals with the In the pharmacological tests, the products were adminis new Substances, no hypotension reactions nor the algogenic tered to animals by local injection in a physiological Solu activity possessed by prostaglandins were observed. In fact, tion. differently from PGE, the new derivatives of the invention were inactive in pain-induction tests. The control groups were treated with a physiological The examples below explain the purpose of the invention Solution. and should not be understood as a limitation of Same. Prostaglandin E, sodium nitroprusside and SIN-1, EXAMPLE 1. chemically defined as 3-(4-morpholinyl)Sydnone imine, which is the active metabolite of molsidomine, were used as Synthesis of 2-nitroxyethyl ester of prostaglandin 15 reference products. E. EXAMPLE 2 O

Relaxing effect in vitro on isolated human --N-N-N-C-O-CH-CH-ONO cavernoSuS artery and cavernoSuS corpus CH The method described by Hempelmann R. G. et al., European Journal of Pharmacology, 1995, 276, 277-280, 25 was followed using erectile tissues from patients Subjected to Surgery. 19.1 mg (0.0539 mmoles) of PGE was dissolved in 0.7 The cavernoSuS arteries were isolated and cleaned of the ml of absolute acetone in a 5-ml flask. 11.5 mg (0.0604 Surrounding connective tissue. Segments about 2-mm long mmol) of p-toluenesulphochloride, 12 mg (0.01188 mmoles) of triethylamine and 8 mg (0,9748 mmoles) of were obtained and mounted in a myograph. 2-nitroethanol were then added to the Solution. The flask was After building a diameter/tension curve, the artery Seg closed and the reaction mixture was stirred for 22 hours at ments were adjusted to a diameter corresponding to 90% of room temperature. At the end the Solvent was evaporated off that reached in the presence of a trasluminal pressure of 100 under vacuum, the residue was treated with 3 ml of water mmHg. After a stabilisation period of about 60 minutes, a and the mixture was extracted with ethyl acetate three times 35 contraction was induced by the addition of 3x10'Madrena using 7 ml each time. line. After 15 minutes, the test compounds were adminis The pooled organic extracts were washed with 1 ml of tered at a concentration of 10M and the per-cent relaxation water and then 1.5 ml of a Saturated NaCl Solution. After induced by the administration of the test product was recorded for each. The results are shown in Table 1. drying over Sodium Sulphate, they were evaporated off to 40 dryneSS under vacuum. Another Set of experiments was conducted according to The oily residue which was obtained was dissolved in the the same methodology, using isolated Strips of cavernous lowest amount of dichloromethane and chromatographed tissue about 3x3x5 mm in size Suspended isometrically, with using a small column packed with 4g of silica gel (Silica gel application of a 5-10 mN tension in baths for isolated 60 A, 230-400 mesh). Dichloromethane was used as the 45 organs. The results are shown in Table 2. initial eluant followed by a mixture of dichloromethane and ethyl acetate which was gradually enriched with the Second In both experimental models an inhibitory effect of the component up to eluting with pure ethyl acetate. The column adrenalin-induced contraction following either treatment with PGE or administration of the nitric-acid-donor SIN-1 was then eluted with a mixture of ethylacetate/methanol, was found. The PGE derivative according to the present gradually enriched with methanol, up to using the pure 50 alcohol. The fractions were analysed by TLC on silica gel invention is shown in the tables by the abbreviation (Silica Gel 60 Fs), using the eluting mixture ethyl-acetate/ NO-PGE. acetic-acid 20/0.5. The test tubes containing the reaction This compound showed an effect Superior to both native product were those containing the eluates with pure ethyl prostaglandin and SIN-1. acetate. Said eluates were joined together and the Solvent 55 was evaporated off to obtain 6 mg of a colourless oil (yield TABLE 1. 25%) having an Rf in the above TLC elution system equal Inhibitory effect of some derivatives on isolated to 0.38. The H NMR spectrum (CDOD) shows all signals human cavernosus artery pre-contracted with 3 x 10 Madrenalin corresponding to PGE (ppm): 56 (m, 2H), 4–4.2(m.2H), for each treatment group n = 5 replications 2,6-2,8(quartet, 1H), 2.0-2,4(m), 1.2–1.8(m). Furthermore, 60 two multiplets centred at Ö=4.75 (2H) and Ö=4,4(2H) inhibition of contraction respectively, corresponding to the two methylene groups of Treatment (%) 2-nitroethanol esterified with the carboxylic group of PGE, 10M PGE, 19 4 were observed. 1OM SIN-1 36 - 7 I.R. spectrum: 3382 cm (OH), 2858-2930 cm 65 10M NO-PGE, 41 - 9 (-CH-, -CH, -CH-), 1774 cm (C=O ester), 1773 cm (group C=O in a five atom ring), 1634 and 1280 cm US 6,211,233 B1 9 10 After injection, at pre-determined time intervals (0.5, 1,2 TABLE 2 and 3 hours), the animals were observed for the presence of erection and evaluation of the relevant per-cent extent Inhibitory effect of some derivatives on isolated according to the following Scheme: human cavernosus tissue pre-contracted with 3 x 10 Madrenaline for each treatment group n = 4 0%=penis not visible 25%=glans visible inhibition of contraction 50%=penis protrusion equal to about half the complete Treatment (%) lenght 10M PGE, 52 - 5 3 x 10M SIN-1 41 6 1O 75%=penis protrusion not complete, but greater than half 10M NO-PGE, 71 - 6 the lenght 100%=complete penis protrusion The results are given in Table 4 and show that the EXAMPLE 3 compound of the invention had a Superior activity to that of 15 the reference compound. Evaluation of induced erection activity and of hypotensive effect in rats TABLE 4 The method described by Pineiro et al., European Urology Average per-cent values of extent of erection 1993, 24, 492-499, was used. Male rats weighing about 350 observed at different time intervals after intracavernosus g (5 animals/group) were anaesthetised with urethane and administration of PGE derivatives in rabbits maintained at a temperature of 37 C. throughout the test. 3O The cavernoSuS corpuses were exteriorized by perineal Treatement minutes 1 hour 2 hours 3 hours Section. The right cavernoSuS corpus was connected to a preSSure transducer using a heparinised catheter and the left Controls 4 6 O% O% O% 25 PGB 20 ug 6 13% 4% O% one was connected using a PE-10 plastic tube to a Syringe by NO-PGE, 6 92% 79% 67% 46% which the products were administered. 20 lig The right carotide artery was cannulated and connected to a pressure transducer to measure the Systemic blood pres Sure. The products were administered intracavernously at a EXAMPLE 5 volume of 0.03 ml at a 10M concentration and the intracavernous pressure and Systemic blood pressure were Effect on painful response of the compound of the monitored. The results given in Table 3 show that PGE was invention in rats slightly active in this model, while Sodium nitroprusside induced a remarkable erection activity. Both derivatives The conventional method of Randall-Selitto modified as caused a drop in Systemic blood pressure, which was par described in Duarte I. D. G. et al., European Journal of ticularly marked in the case of nitroprusside. NO-PGE 35 Pharmacology, 1990, 186, 289-293, was used to determine showed an effect Superior to both PGE and sodium nitro the potential activity on painful response of the compound. prusside on intracavernous preSSure, while causing a non The test includes the application of a steady 20-mmHg Significant drop in Systemic blood pressure, which was preSSure to a back paw of rats. PreSSure application was comparable to that of Starting Prostaglandin, and was Sig discontinued when the animals appeared to react and the nificantly lower than that of nitroprusside. 40 response latency time, which was the parameter used to evaluate the analgesic or hyperalgesic effect of the test AS a result, the products of the invention have been shown product, was recorded. Immediately after, the product was to possess a pharmacodynamic profile which is more favour administered by the intradermal route in the Subplantar area able compared to the reference compounds. (administration volume 2.5 ul containing 0,1 ug of the test 45 product). The test was repeated 3 hours later. TABLE 3 The results given in Table 5 show that PGE reduced the Effect of intracavernosus treatment of various latency time, i.e. acted as a hyperalgesic agent. Sodium derivatives on intracavernosus pressure (P) and systematic nitroprusside caused a slight nonsignificant increase in blood pressure (P) in anaesthetised rats (n = 4 latency time. NO-PGE was inactive, thus showing that the Increase in Drop in 50 NO group in the PGE molecule reduced the hyperalgesic intracavernous systemic P property. In the table, the column identified by an “n” shows Treatment P (cm H2O) the number of animals used for each treatment. 10M sodium nitroprusside 27 + 3,7 51 + 7.8 TABLE 5 10 MPGE, 0.7 + 0.4 18.2 + 2.2 10M NO-PGE, 36 - 14 9,1 + 3,1 55 Effect of the compound of invention and reference substances on modified Randal-Selitto test

reaction time EXAMPLE 4 Product (ug?paw) change (seconds) Inducted erection activity in rabbits 60 PGE, (0,1) 8 -17 - 2 Sodium 8 +4 + 2 The method described by Stackl W. et al., Urological nitroprusside (5) Research 1988, 455-458, was used. Male rabbits weighing about 2 Kg (n. 6 animals/group) were injected 1 ml of NO-PGE, (0,1) 1O O physiological Solution containing 20 lug of the test products into the right cavernoSuS corpus. During the injection, 65 The derivatives were active in various tests useful to complete penis protrusion was observed, which was con evaluate the potential pharmacological induced-erection sidered as 100% erection. activity versus reference compounds. US 6,211,233 B1 11 12 Unlike Sodium nitroprusside, the invention compounds Ro and Rao are equal to or different from each other and induced no hypotension at the pharmacologically active are equal to R; when R or Rs is a free Valence, and doses in the experimental impotency models. R or Rao is a free Valence, there is a double bond The invention compounds showed no pain effects which between C and Cs; could be found after the administration of PGE in experi 5 mental tests in rats. R2, R22, R2, and R2 are equal to or different from each What is claimed is: other and are equal to R; 1. Compounds of the formula Rs and Rae are equal to or different from each other and are equal to R, but both Rs and R cannot be a free Valence, A-X-NO, (I) R, is a linear or branched alkyl having one to six carbon wherein A is atoms, B is equal to the group O-(a keto group with the carbon R(CRRO)(COX), (II) 15 atom at position 9 of the prostaglandin molecule) or is OH or -O-, whereint and u are integers and are equal to 0 or 1, when no aliphatic chain C7-C is at position 8, there is in X=O, NH, NR wherein R is a linear or branched its place an alkylaromatic residue: alkyl having form 1 to 10 carbon atoms, RandR, are equal to or different from each other and are H, or a C-C alkyl radical and R is a radical having the (IV) following formula: o (CRaRb)mi (III) 25 R25 Rs R13 R3 R19 | R15 B which is bound to formula (III) (B=-O-) in the following way: R26in-s-s-1 R6 R14 R4 R20 R16 (V) R9 in R21 C14 C16 R17 o (CRaRb).m.1 fl.1. 1. 18 1 R10 R12 C17 R8 R2 l 35 18 9-8 wherein mo is an integer having a value of 0 or 1; and when wherein m is an integer from 1 to 6, t=1, u=0 and mo=1: 40 R=H; an alkyl having from 1 to 6 carbon atoms or a free R, and R are equal to or different from each other, and Valance; are as defined above, when t=0, u=1, and mo=1 the R=OH, O- such as to form with R when R is a free meanings of the various Substituents are as defined Valance, and with the carbon atom at position 15 a above, when t=1, u=0, and mo=0 the meanings of the C=O group; 45 Various Substituents are as defined above and C is R and R are equal to or different from one another and bound, optionally by a bridging group -O-, to an are equal to R or one of them is a bond O-, and the aromatic radical or an alkyl-aryl radical, where the aryl other is a free Valance So that with the carbon atom C. can be Substituted, Said aryl radical can also contain they form a C=O group; heteroatoms, such as O or N; the alkyl of the alkyl-aryl Rs and R are equal to or different from one another, and 50 radical is an aliphatic chain from 1 to 3 carbon atoms, are equal to R when both Rs and R are each a free X of formula A-X-NO is a bivalent connecting Valence, Rs and R form a double bond between Cs and bridge, chosen from the following: Co.; R7, Rs, Ro, and Ro are equal to or different from each other, and have the Same meaning as R; 55 when R, or Ro, and at the same time Rs or Ro are each a free Valence, there is a double bond between C and where Y is a linear or whenever possible branched C-Co C14: alkylene oxygen terminated, or is a C-C, cycloalkylene 60 oxygen terminated optionally Substituted; R=R or OH; R. R., Ris, and R are equal to or different from each other, and are equal to R; when R or Rs, and at the Same time R or R, are each a free Valence, there is a double bond between C and C.; 65 R7 and Rs are equal to or different from each other and are equal to R; US 6,211,233 B1 14 where n is an integer from 0 to 3, formula (IV) as shown in (V); R =H; R =CH; R, R2, R2, R2, being each a free Valence to form a triple CHO bond between Cs and Co.; R thus defined is known as the residue of Beraprost; 21 when t=0; u=1 and mo-1: R=R=H and R is the residue -(CH2-CH-CH-O)- of Misoprostol, R thus defined is known as the residue Sa. of Rioprostil, Se ONO2 HOOC CH-, when t=1, u=0 and mo-0: when R is the residue of Arbaprostill except that R=H; 1O Rio or Rao is a free Valence or H, So that between C. where inf is an integer from 1 to 6; and and Cs there is a double bond; C is linked to a group -O-A, wherein Al=phenyl; R thus defined is known - (CH-CH-O)- as the residue of Enprostil; when R is the residue of Arbaprostill except that B is OH; 15 R=H, C is linked to a group -CH2-A, where A is phenyl; it is defined a radical known as the residue of where R=H or CH, and nf is an integer from 1 to 6. Latanaprost, 2. Compounds according to claim 1 wherein the prostag when in the formula of Enprostill R-R-H; it is defined landin residues R are the following: a radical known as the residue of Sulprostone. when in formula (II) t=1 u=0 and in formula (III) mo-1: 3. A compound according to claim 1 where R is the B is O= (keto group with Co.); R7, Rs, Ro and Ro are residue of Prostaglandin E. Such as to given a double bond between C and C, 4. A method for treating cerebrovascular and cardiovas R is OH; R, is CH; the Substituents of the carbon cular disorders, glaucoma, and peptic ulcer disorders, and a atoms of the C-C, and Co-Co aliphatic chains are H, 25 method for inducing abortion, comprising administering to R thus defined is known as the residue of Prostaglandin a patient an effective amount of a compound of claim 1. E1, 5. Pharmaceutical compositions containing as the active or, by putting in the formula of ProStaglandin E, R=CH ingredient compounds of claim 1 and a pharmaceutically and R, R, Rs, R. Such as to give a double bond acceptable carrier. between Cs and Co., R thus defined is known as the 6. A method for treating impotence comprising adminis residue of Arbaprostil; tering to a patient an effective amount of a compound of the or, by putting in the formula of Arbaprostill R=Rs=Ro= formula: Ro=H; R and R are Such as to form the group C=O with Cs; B is OH; R,-CH7; R thus defined is known A-X-X-X-NO. (I) as the residue of Unoprostone; 35 wherein A is or, by putting in the formula of Arbaprostill R=R=CH, R=H, R thus defined s known as the residue of Trimoprostil; R(CRRO)(COX), (II) or, when in the formula of Arbaprostill B is OH; R =H; whereint and u are integers and are equal to 0 or 1, R thus defined is known as the residue of Prostaglandin 40 X=O, NH, NR wherein R is a linear or branched F2c. alkyl having form 1 to 10 carbon atoms, or, when in the formula of Prostaglandin F. B is O= R, and R, are equal to or different from each other and are (keto group with Co.); R thus defined is known as the H, or a C-C alkyl radical and R is a radical having the residue of Prostaglandin R; following formula: or, when in the formula of Arbaprostill B is OH; R thus 45 defined is known as the residue of Carboprost; (III)

or, by putting in the formula of Arbaprostill R=H; R,-H; Ro=CH, R=R=Rs=Re=H; R27–CHS, R=Re=H and R=Rs being free Valences Such as to form a 50 double bond between C and C.; R thus defined is known as the residue of Limaprost; or, by putting in the formula of Trimoprostill R=R=Rs= Re=H, and positioning the double bond between C and C instead that between Cs and C, R thus defined is 55 known as the residue of Gemeprost, or, by putting in the formula of Arbaprostill R=R=H; R=OH; R =CH, R=Rs=R=R=H; R thus defined is known as the residue of Misoprost, or, by putting in the formula of Arbaprostill R=H; Rs= 60 CH, R7–CHs; R and R are Such that one of them wherein mo is an integer having a value of 0 or 1; and when is a free Valence and the other is a single bond with an t=1, u=0 and mo=1: oxygen atom So that together with the carbon atom C. R=H; an alkyl having from 1 to 6 carbon atoms or a free form a keto group C=O; R5=R6=H, R thus defined is Valance; known as the residue of Ornoprostil, 65 R=OH, O- such as to form with R when R is a free or, as in Arbaprostil, without the C-C aliphatic chain Valance, and with the carbon atom at position 15 a and the carbon atoms Co-Cs linked to the group of C=O group; US 6,211,233 B1 15 16 R and R are equal to or different from one another and R, and R, are equal to or different from each other, and are equal to R or one of them is a bond O-, and the are as defined above, when t=0, u=1, and mo=1 the other is a free Valance So that with the carbon atom C. meanings of the various Substituents are as defined they form a C=O group; above, when t=1, u=0, and mo=0 the meanings of the Rs and R are equal to or different from one another, and Various Substituents are as defined above and C is are equal to R when both Rs and R are each a free bound, optionally by a bridging group -O-, to an Valence, Rs and R form a double bond between Cs and aromatic radical or an alkyl-aryl radical, where the aryl Co.; can be Substituted, Said aryl radical can also contain R7, Rs, Ro, and Ro are equal to or different from each heteroatoms, such as O or N; the alkyl of the alkyl-aryl other, and have the Same meaning as R; 1O radical is an aliphatic chain from 1 to 3 carbon atoms, when R, or Ro, and at the same time Rs or Ro are each X of formula A-X-NO is a bivalent connecting a free Valence, there is a double bond between C and bridge, chosen from the following: C14: 15 R=R or OH; R., R., Rs, and R are equal to or different from each other, and are equal to R; when R or Rs, and at the Same time R or R, are each a free valence, there is a double bond between C and C.; where Y is a linear or whenever possible branched C-Co R7 and Rs are equal to or different from each other and alkylene oxygen terminated, or is a C-C-7 cycloalkylene are equal to R; oxygen terminated optionally Substituted; Ro and Rao are equal to or different from each other and are equal to R; when R or Rs is a free Valence, and 25 Rio or Rao is a free Valence, there is a double bond between C and Cs; R2, R22, R2s, and R2 are equal to or different from each other and are equal to R; Rs and R are equal to or different from each other and are equal to R, but both Rs and R cannot be a free where n is an integer from 0 to 3; Valence, R, is a linear or branched alkyl having one to six carbon CHO atoms, B is equal to the group O= (a keto group with the carbon 35 21 atom at position 9 of the prostaglandin molecule) or is - (CH-CH-CH-O)- OH or -O-, yS-X when no aliphatic chain C7-C is at position 8, there is in HOOC CH-, ONO its place an alkylaromatic residue: 40 (IV)

(CH- CH- CH- O)nf o cell-O) 45 ONO2 which is bound to formula III (B=-O-) in the following way: where inf is an integer from 1 to 6; and 50 (V) -(CH-CH-O)- (CRaRb)n 1

where R=H or CH, and nf is an integer from 1 to 6. wherein m is an integer from 1 to 6,