GB2279345A

GB2279345A - Cyclohexanecarboxylic acid derivatives

Info

Publication number: GB2279345A
Application number: GB9412367A
Authority: GB
Inventors: Bugno Cristina Di; Alessandro Subissi; Marco Criscuoli; Luigi Turbanti; Raffaello Giorgi; Fabrizio Bonaccorsi; Germano Carganico
Original assignee: Laboratorio Guidotti SpA
Current assignee: Laboratorio Guidotti SpA
Priority date: 1993-06-21
Filing date: 1994-06-20
Publication date: 1995-01-04
Also published as: FR2706897A1; FR2706897B1; ITMI931329A1; IT1264860B1; GB9412367D0; DE4421515A1; ITMI931329A0

Description

2279345 -l CYCLOHEXANECARBOXYLIC ACID DERIVATIVES AND COMPOSITIONS The

present invention refers to a series of cisand trans-2-[[[2(hydroxyamino)-2-oxoethyllalkylaminol- carbonyllcyclohexanecarboxylic acid derivatives and of enantiomers thereof having antihypertensive activity, their preparation process and their use in pharmaceuti- cal compositions.

The compounds of the invention are represented by the general formula 1 R 3 Cl\ NH R 1 1 1 oi:, ILocv' N,%.% C."'92 v COOR 1 wherein R 1 is C 1 -C 4 alkyl; R 2 is H; C 1-C 12 alkyl; C 3-C6 cycloalkyl; phenyl; C 1-C 4 alkoxymethyl; 2-tetrahydrofurylmethyl; 2-di(C 1-C 4 alkyl)aminoethyl; -CH(R 4)OCOR 5; - CH(R 4)COR 6; N-methylbenzamidylmethyl; R 3 is hydrogen; (C 1-C 6 alkoxy)carbonyl; benzyloxycarbonyl; (C 1-C 12 alkyl)carbonyl; adamantylcarbonyl; phenylcarbonyl optionally substituted by 1 to 3 substituents selected from Cl, NO 2 and OCH 3; 3-pyridyl- carbonyl; R 4 is hydrogen; C 1-C 6 alkyl; R 5 is C 1-C 12 alkyl; adamantyl; -(CH 2)0-2 C CC6 cycloalkyl; (C 1-C 6 alkyl) -COOH; (C 1-C 6 alkyl)-CONR 4; 2-, 3- 2 or 4-piperidinyl; 2-, 3- or 4-piperidin-l-benzoyl; phenyl optionally substituted by 1 to 3 substituents selected from R 4. OCH 31 OH, 0COO(C1C4 alkyl), Cl; cis and trans 2-([[2-(hydroxyamino)-2-oxoethyll(C 1-C 4 alkyl)aminolcarbonyllcycloexyl; C 1-C 6 alkoxy; C 4-C6 cycloalkoxy optionally substituted by 1 to 2 substituents selected from R 4; biphenyl; R 6 = -NR 7 R 8; 1-piperidinyl; 1-morpholinyl; R 7 and R 8 7 which are the same or different, are H; C 1-C 6 alkyl; phenyl; C 1-C 4 hydroxyalkyl; CH 2 CON(R 4); CH(COOH)CH 2 Ph; OH and combinations thereof; with the provisos that:

1 1 R 2 and R 3 are not contemporaneously H; when R 1 is methyl and R 3 is hydrogen, R 2 is different from methyl and from acetyloxymethyl; when R 1 is ethyl and R 2 is hydrogen, R 3 is dif f erent from acetyl; when R 1 is methyl, R 2 and R 3 are not contemporaneoulsy CH 3 The invention also comprises the non-toxic salts, the single enantiomers or diastereoisomers and relative mixtures of compounds 1. The compounds excluded from the previous provisos were disclosed in US 5,095,137 where their favourable pharmaceutical propertieswere not however either di- scussed or recognized.

In the compounds of f ormula 1, R 1 is pref erably methyl or ethyl; R 2 is preferably hydrogen; C 3-C12 alkyl; C 3-C6 cycloalkyl; phenyl; c 1-C 4 alkoxymethyl; 2 tetrahydrofurylmethyl; 2-di(C 1-C 4 alkyl)aminoethyl; CH (R 4) OCOR 5; CH (R 4) COR 6; R 3 is preferably hydrogen, 1 3 (C 1-C 6 alkoxy)carbonyl; benzyloxy carbonyl; (C 1-C 12 alkyl)carbonyl; adamantylcarbonyl; phenylcarbonyl optionally substituted by 1 to 3 substituents selected f rom Cl, NO 2 and OCH 3; R 4 is preferably hydrogen or methyl; R 5 is preferably C 4-C12 alkyl; - (CH 2)1-2-C4-C6 cycloalkyl; (C 1-C 6 alkyl)- COOH; (C 1-C 6 alkyl)-CONR 4; 2-, 3- or 4piperidinyl; 2-, 3- or 4- piperidin-l-benzoyl; phenyl optionally substituted by 1 to 3 substituents selected from R 4 p OCH 31 OH, OCOO (Cl-C4 alkyl), Cl; cis or trans 2- [[[2-(hydroxyamino)-2-oxoethyl](C 1-C 4 alkyl)amino]carbonyllcyclohexyl; C 1-C 6 alkoxy; c 4-C6 cycloalkoxy optionally substituted by 1 or 2 substituents selected from R 4; R 6 is as defined above, with the proviso that R 2 and R 3 are not contemporaneously hydrogen.

Preferred classes of the compounds of formula 1 those wherein:

A) R 3 is hydrogen and R 2 is C 3 -C 12 alkyl, preferably c 6-C12 alkyl; 2-tetrahydrofurylmethyl, methoxymethyl, 2-diethylaminoethyl or a group of formula CH (R 4) OCOR 5, wherein R 4 is hydrogen or methyl and R 5 is c 4C12 alkyl; - (CH 2)0-1 cyclohexyl, (C 3-C4 alkyl)-COOH, (C 3-C4 alkyl)CONEt 2; piperidinyl; piperidin-l-benzoyl; adamantyl; N-methyl benzamidylmethyl; phenyl optionally substituted by 1 to 3 substituents selected f rom R 4 jI OCH 31 OH, OCOO(C 1-C 4 alkyl), Cl; diphenyl; B) R 3 is hydrogen and R 2 is a group CH (R 4)COR 6, wherein R 4 is hydrogen and R 6 is -NR 7 R 8, wherein R 7 and R 8, which are the same or dif f erent, are hy- drogen; C 1-C 6 alkyl; phenyl; diphenyl; C 1-C 4 hy- 4 c) droxyalkyl; CH 2 CONH 2; CH(COOH)CH 2 Ph; OH; or R and R 8, considered together with the N atom to which they are linked form a 1-piperidinyl or lmorpholinyl ring; R 3 is hydrogen and R 2 is a group CH (R 4)OCOR 5 wherein R 4 is hydrogen or methyl and R 5 is c 1-C 6 alkoxy; C 4-C6 cycloalkoxy optionally substituted by 1 or 2 substituents selected from R 4; D) R 2 is hydrogen and R 3 is (C 1-C 4 alkoxy)carbonyl; benzyloxycarbonyl; (C l-c- 12 alkyl)carbonyl; phenylcarbonyl, optionally substituted by 1 to 3 substituents selected from Cl, NO 2 and OCH 3; adamantylcarbonyl; 3- piridylcarbonyl.

The starting compounds, namely the cis-2-[[[2(hy is droxyamino)-2-oxoethyllmethylamino]carbonyl]cyclohe- xanecarboxylic acid I and trans-2-[[[2-(hydroxyamino)2oxoethyllethylamino]carbonyl]cyclohexanecarboxy lic acid II and particularly their biologically active stereoisomers, respectively (lS,2R)- of compound I and (1R,2R)- of compund II, disclosed in the italian patent 1 224 627 (4-10-1990) and in US 5,095,137 (10-3-1992) exhibit a remarkable ACE inhibitory activity and repre sent a new non-aminoacidic structure of ACE-inhibitors, turning out therefore to be potential new therapeutic agents for the treatment of hypertension.

The compounds of formula 1 have improved proper ties which make them particularly useful for the treat ment of hypertensive diseases and of heart failure, diabetic nephropathies, cardiac infarct, cardiac hyper trophy, vascular proliferation and of diseases of the Central Nervous System.

For the intended therapeutic uses, the compounds of the invention are formulated in conventional pharmaceutical formulations suited to the oral, parenteral or transdermal administration, using known methods and excipients, disclosed for instance in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., NY, USA, XVII ed. The daily posology will depend on several factors, such as kind and seriousness of the disease to be treated., patient's conditions generally, it will range from divided in more administrations.

The processes, which are a further object of the invention, for the preparation of the compounds of formula 1 comprise the conversion, according to Scheme I, of the benzylated product 2 into the corresponding ester derivative 3, by reaction with a suitable halo derivative (chlorine, bromine or iodine, preferably chlorine) in the presence of an organic base, preferably triethylamine or DBU, in an organic solvent such as THF, DMF or acetonitrile, preferably DMF, at a temperature from 0 to 1000C, preferably at room temperature.

The starting product 2 is already known (US 5,095,137) and the halo derivatives exemplified as R 2 Hal are commercial products or they may be prepared with known procedures.

The so obtained product 3, suitably purified, subjected to hydrogenolysis of the benzylic protective group by reaction with hydrogen in the presence of a suitable catalyst, in solution of an organic solvent such as THF or ethyl acetate, yields the compounds of the invention 1 with R 3 =H.

(weight, sex, age) but, 1 to 500 mg, optionally 6 OCH2Ph 'NH R' H2. Pd/C is 2 HO SCHEME I RZM, BM OCH2Ph 1 "'1NH R 0- 1 1 2 OOR COOH HO.

R 0 00Fe 1 3 SCHEME I I NH R, R W. Base 0- WO \ NH R, 1 1 1 1 N t,, c--,C4 eoeNN,..C 0 COOH 0 COCH 4 1 Another process (Scheme II) for preparing the com pounds 1 wherein R3=H comprises the reaction of com pound 4, already known, with an R3Hal derivative, whe rein Hal is preferably chlorine, in the presence of a suitable proton acceptor, such as aqueous NaOH, NaH or DBU, at a temperature from 0 to 50C, preferably from 0 to 300C.

The above mentioned derivatives R 3 Hal, i. e. acyl halides or haloformiates, are commercial productsor are prepared by known methods.

The compounds of the invention were evaluated by 1 7 in vivo tests suited to detect in animals the ACE-inhi bitory activity expressing their potential antihyper tensive properties, as well as to compare their biolo gical properties with that of the compounds disclosed in US 5,0951,37.

As already known, ACE-inhibitors exert their anti hypertensive activity by inhibiting the ACE-catalyzed biosynthesis of the potent endogenous vasoconstrictor angiotensin II from the precursor angiotensin I. The inhibitory action is due to the capacity of these mole cules to bind, by means of specific functional groups, to the enzyme active site in competition with angioten sin I.

The enzymatic activity of the ACE inhibitors is directly determined on the enzyme by in vitro tests, whereas the ACE-inhibitory action is evaluated in vivo by measuring the decrease of the pressure increase in duced in the animals by repeated angiotensin I admini strations.

The compounds of the invention studied on the ex perimental animals showed an ACE-inhibitory activity both after i.v. and after oral administration. In table I the pharmacological results for a broad selection of the most significant compounds are reported.

From the values in the Table, it turns out that also the compounds of the invention have a very good bioavailability after oral administration as shown by the low values of the ED 50 os and ED 50 i.v. values.

The compounds of the invention were inactive on the in vitro ACE-inhibition test, probably because of the chemical changes to their "binding" groups.

8 In the above cited US patent, some compounds derivatized on the carboxy or on the hydroxamic moiety (namely compounds of Examples 10, 12-16, 4243 of said US patent) were also disclosed. These compounds were studied only as far as the effects of the chemical changes on the affinity for ACE were concerned but the in vivo ACE-inhibiting activity per os was not determined. These compounds have now been studied also after oral administration and compared with the compounds of the present invention: the results show that the previously described "derivatized" compounds do not have a better bioavailability after oral administration in comparison with their precursors and cannot be compared in this respect with the compounds of the present in- vention.

1 Table I - Effect on the pressure response induced by angiotensin I in the rat: (ED50), time of maximal effect (T max) and duration (Tl/2) of the compounds administered by the intravenous, intraduodenal and oral route.

Example a) I.V. c) TI/2d) I.D. OS n. EDSO Tmax ED50 Tmax T1 /2 ED50 b) T Duration pmol/kg min min pmol/kg min min pmol/kg max min min 13 0.96 1-6 47 3.2 6 27 8.5 20-30 110 68 2.7 1-6 25 1.9 16-21 45 3.2 20 80 39 0.35 1 20 3.1 30 60 8.1 20-30 80 0.21 1 15 3 11 60 9.3 30 70 38 0.57 1 22 3 6-11 55 7.1 20-30 80 69 1.3 1-6 60 2.4 6-11 50 4.6 2030 70 0.57 1 60 1.2 16-21 60 1.5 30-40 12 0.83 1-6 60 2.3 6-21 60 2.1 10-20 0.51 1 36 3.6 16 60 7.4 73 1.9 1 60 2.2 6 60 3.9 20-30 90 2.4 6 60 3.7 11 60 6.5 20-30 80 24 1.2 4.6 13 7.4 1.9 5.3 49 8 8 1 10 10 14 9.4 20-30 100 - (continue) - Example a) I.V. C) d) I.D. b) Os Duration n. ED50 T max T1/2 ED50 T max T1/2 ED50 Tmax pmol/kg min min pmol/kg min min pmol/kg min min 72 3.9 6 40 2.1 11 60 8.8 30 90 74 4 1 20 7 9.1 16 0.59 1 20 6 1.1 3.4 20 34 4.4 11 2.2 33 4.8 36 6.4 20 C) 37 2.1 10 66 3.8 20 67 2.8 20 77 3.8 20 1.2 3.6 43 0.62 3.4 1.6 8.6 47 0.24 3.3 19 0.38 2.7 44 0.38 1.4 48 0.95 2.2 (continue) Example a) I.V. C) d) I.D. b) OS Duration n. ED50 Tmax T1/2 ED50 Tmax T1/2 ED50 Tmax pmol/kg min min pmol/kg min min pmol/kg min min 46 0.22 2. 5 41 0.10 1 15 2.6 10 42 0.12 1 15 0.93 10-20 58 0.76 6-11 40-60 6 30 59 8.3 30 4.5 10 17 2 20 18 1.2 20 Reference compounds Ex. 12 >37 >11 Ex. 14 4.4 6 35 30 20-40 >60 >8.8 Ex. 15 1 50 16 6-11 >60 10.3 20 70 Compounds disclosed in the cited examples of US 5,095,137 12 a) Pharmacological method: i.v. and tion The animals were anesthetized with ethylurethane (1.5 g/kg i.m.). The right femoral vein and the left jugular vein were incannulated for the administration of pentolinium. tartrate (0.1 mg/kg/min.), angiotensin I and the compound under test. A catheter was inserted into the left carotid artery and connected to a Benthley Trantec 800 (U. Basile) pressure transducer. After 301, reached the equilibrium, angiotensin 1 (310 mg/kg) was injected at 5 minutes interval until three reproducible responses were obtained.

One minute before the subsequent angiotensin-I administration, the compounds to be tested were administered by intravenous or intraduodenal route. The angiotensin-I injections were repeated until the pressure response returned to the basal value. One animal was used to test each single dose of each compound. The ED 50 values were calculated from the peak of the inhibitory activity.

b) Pharmacological method: os administration The animals fasting since 16 hours were moderately anesthetized with ethyl ether to incannulate the left jugular vein and the left carotid artery. The other ends of the cannulas were driven under the skin and brought to the outside at the level of the neck back side. The rats were placed in single cages and the mean blood pressure was measured as previously described. After one hour, reached the equilibrium, angiotensin 1 (310 mg/kg) was injec- i.d. administra- 13 is ted at 10 minutes interval until three reproduci ble responses were obtained.

Ten minutes before the subsequent angiotensin administration.. the compounds to be tested were orally administered by gastric tube. The angiotensin-I injections were repeated every 10 minutes for 2 hours after the drug administration.

c) Time of onset of the maximum effect, in minutes after administration (1-6 means the interval between the first and the sixth minute).

The present invnetion is further illustrated by the following examples.

EXAMPLE 1

General procedure for the preparation of compounds of formula 1 according to process scheme I.

1 st step_: 8.6 mmoles of halo-derivative (R 2 -Hal) in 10 ml of solvent were added to a mixture of 8.6 mmoles of the starting compound 2, having the convenient stereoisomery, 8.6 mmoles of base, optionally in the presence of 1.72 mmoles of NaI as catalyst.

The reaction mixture was stirred for the time length and at the temperature as shown in Table 2.

The reaction mixture was then evaporated to dry- ness and the residue was added with ethyl acetate and a saturated NaCl solution.

After separating the phases, the organic one was washed with 5% aqueous HCl, a saturated NaHCO 3 aqueous solution, a 5% Na 2 S 2 0 3 solution (in the event NaI is used as catalyst), water and finally dried over MgSO 4 After vacuum-evaporating off the solvent, the crude product 3 was used as such in the subsequent 14 stage, otherwise it was _purif ied by f lash-chromato graphy on a silica gel column.

2, nd step: a solution of 2.1 mmoles of product 3 in ml of the convenient solvent, was hydrogenated at ambient pressure and room temperature in the presence of 10% w/w of 10% Pd/C. After the theoretical hydrogen absorption the suspension was filtered, concentrated and vacuum-evaporated to dryness.

The product listed in Table 2 below, obtained with the above described procedure, resulted pure by HPLC and TLC analysis, further 'H-NMR analysis confirmed the expected structure and elemental analysis (C, H, N) was in accordance with the theoretical values.

EXAMPLE 2

General procedure for the preparation of compounds of formula 1 according to process scheme II.

Method A (Compounds 24, 26, 28, 58-65 and 76).

22.5 mmoles of 1 M NaOH were added to an aqueous solution, cooled to OOC, of 10.7 mmoles of the starting compound 4 and the resulting solution was added dropwise with 10 ml of a THF solution containing the halo-derivative R 3 -Hal. The mixture was maintained un der stirring at VC for the time length shown in Table 3 below, then it was acidified, maintaining the same temperature, with 2% HCl and extracted with methylene chloride (4 x 40 ml). The organic phases were gathered and washed with water (10 ml), dried over MgSo 4 and evaporated at reduced pressure.

Method B (Compound 25) 14.2 mmoles of DBU were added to a solution of 5.7 mmoles of compound 4 in DMF (20 ml) and a solution of 5.7 mmoles of halo-derivative (see Table 3) in DMF (10 ml) was added drop by drop at room temperature.

The reaction mixture was kept under stirring at room temperature for 3 hours, after which the solvent was evaporated off and the residue, added with methylene chloride, was washed with 5% HCl, water, dried over MgSO 4 and evaporated to dryness.

Method C (Compound 27) 16.8 mmoles of NaH (60% suspension in paraffin) were added portionwise to a solution of 8.0 mmoles of compound 4 in DMF (30 ml) and subsequently a suspension of 8.0 mmoles of nicotinoyl chloride hydrochloride in DMF (20 ml) was added drop by drop. The reaction mixture was stirred overnight at room temperature, then diluted with ethyl acetate, washed with a saturated NaCl aqueous solution, water, dried over MgSO 4 and evaporated to dryness.

The crude products obtained with the methods A, B or C in some cases turned out to be already pure, as shown by HPLC and TLC, in other cases they were purified by crystallization from suitable solvents or solvent mixtures. For all the products listed in Table 3, 1 H-MR analysis confirmed the expected structure and elemental analysis was in accordance (T 0.4%) Table 2 3

Preparation of compounds of formula 1 according to scheme I (R Comp. Stereoisomery 1 2 2 n. cpd. 3 R R R Hal cpd. 1 1 Cis-RAC CH 3 -CH 2 OCH 3 C1CH 2 OCH 3 2 Cis-US,2R) CH 3 -CH 2 CH 2 NEt 2 C1CH CH NEt 3 2 2 2 Cis-RAC CH 3 2-tetrahydrofuryImethyl bromofurfurol 4 Cis-RAC CH 3 -CH 2 OCOCH 3 I-CH 2 OCOCH 3 Cis-(lS,2R) CH -CH OCOC(CH Cl-CH OCOC(CH 3 2 3)3 2 3)3 6 Cls-RAC CH 3 -CH 2 OCO(CH 2)3 COOH Cl-CH 20CO(CH 2)3 COOCH 2 Ph 7 Cis-(lS,2R) CH 3 Cl-CH 2 OCO(CH 2)3 CONEt 2 Cl-CH 2 OCO(CH 2)3 CONEt2 8 Cis-RAC CH 3 piperidin-4-carbonyloxymethyl chloromethyl N-benzoyloxy carbonyl-piperidin-4-carbo xylate 9 Cis-(lS,2R) CH 3 N-benzoylpiperidin-3-carbonyl- chloromethyl N- benzoylpipe oxymethyl ridin-3-carboxylate Cis-(lS,2R) CH 3 3,4,5-trimethoxybenzoyloxymethyl 3,4,5- trimethoxybenzoyloxy methyl chloride 11 Cis-(1St2R) CH 3 adamantoyloxymethyl adamantoyloxymethyl chloride 12 cis-(1s,2R) CH 3 -CH(CH 3)OCOCH(CH 2 CH 3)2 Cl-CH(CH 3)OCOCH(CH 2 CH 3)2 (continued) (continued) Comp. Stereoisomery n. cpd. 3 cpd. 1 13 14 is 16 17 18 19 20 21 22 23 29 30 31 R 2 Cis-RAC Trans-RAC Trans-RAC Cis-RAC Cis-(lS,2R) Cis-(lS,2R) Cis-(lS,2R) Trans-(lS,2R) Cis-RAC CisRAC Cis-RAC Cis-(lS,2R) Cis-(lS,2R) Cis-RAC CH 3 -CH(CH 3)OCOC(CH 3)3 CH 2 CH 3 -CH(CH 3)OCOC(CH 3)3 CH 2 CH 3 1-(cyclohexylacetyloxy)ethyl CH 3 CH 3 CH 3 CH 3 CH 2 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 R 2 Hal 1 with R 2 = CH 2-, R CH -CH 20CO0CH 3 -CH 2 OCOOCH 2 C(CH 3)3 -CH(CH 3 WC0OCH 2 CH 3 -CH(CH 3)OCOOCH(CH 3) -CH 2 CON(CH 3)2 -CH 2 COOH -CH 2 CONHCH(CH 2 Ph)COOH -(CH 2) 11-CH 3 -CH 2 OCO(CH 2)3 CH 3 -CH 2 OCO(CH 2)4 COOH I-CH(CH 3)OCOC(CH 3)3 I-CH(CH)OCOC(CH) 1-iodoethy3lcyclohex3y3 acetate 3 with R 1 = CH 3, R 2 = CH 2 C1 CICH 2 OCOOCH 3 ClCH 2 OCOOCH 2 C(CH 3)3 ClCH(CH 3)OCOOCH 2 CH 3 Cl-CH(CH 3)OCOOCH(CH 3)2 Cl-CH 2 CON(CH 3)2 Br-CH 2 COOCH 2 Ph Br-CH 2 CONHCH(CH 2 Ph)COOCH 2 Ph Br-(CH 2) 11-CH 3 10-undecenoyloxymethyl chloride Cl-CH 2 OCO(CH 2)4 COOCH 2 Ph (continued) - (continued) Comp. Stereoisomery 1 n. cpd. 3 R R R Hal cpd. 1 32 Cis-RAC CH 3 piperidin-3-carbonyloxy- chloromethyl N-benzoyloxy methyl carbonylpiperidin-3-carbo xylate 33 Cis-RAC CH 3 -CH 20COPh Cl-CH2 0COPh 34 Cis-US,2R) CH 3 3,5-ditert-butyl-4-hydroxy- 3,5-ditert-butyl-4-hydroxy benzoyloxy methyl benzoyloxymethyl chloride Cis-(lS,2R) CH 3 3,5-dimethoxy-4-ethoxycar- 3,5-dimethoxy-4-ethoxycar bonyloxy methyl bonyloxymethyl chloride 36 Cis-(lS,2R) CH 3 2,6-dimethylbenzoyloxy 2,6-dimethylbenzoyloxymetliyl methyl chloride 37 Cis-(IS,2R) CH 3 2,6-dichlorobenzoyloxy 2,6-dichlorobenzoyloxymethyl methyl chloride 38 Cis-RAC CH 3 -CH(CH 3)OCOC 6 H 11 I-CH(CH 3)OCOC 6 H 11 39 Cis-RAC CH 3 -CH(CH 3)OCOCH 2 c 6 H 11 I-CH(CH 3)OCOCH 2 c 6 H 11 Trans-RAC CH 2 CH 3 -CH(CH 3)OCOC 6 H 11 I-CH(CH 3)OCOC 6 H 11 41 Cis-(lS,2R) CH 3 -CH 2 OCOOCH 2 CH 3 Cl-CH 2 OCOOCH 2 CH 3 42 Cis-(lS,2R) CH 3 -CH 2 -OCOOCH(CH 3)2 Cl-CH 2 OCOOCH(CH 3)2 43 Cis-(lS,2R) CH 3 -CH(CH 3)OCOOCH(CH 3) 2 Cl-CH(CH 3)OCOOCH(CH 3)2 (continued) (continued) Comp. Stereoisomery 1 n. cpd. 3 R R R Hal cpd. 1 44 Cis-(lS,2R) CH -CH(CH)OCOO(CH2) CH Cl-CH(CH)OCOO(CH CH 3 3 3 3 3 2)3 3 Cis-(lS,2R) CH 3 -CH(CH 3)OCOOC(CH 3) 3 Cl-CH(CH 3)OCOOC(CH 3) 3 46 Cis-(lS,2R) CH 3 -CH(CH 3)OCOOCH 2 C(CH 3)3 Cl-CH(CH 3)OCOOCH 2 C(CH 3)3 47 Cis-(lS,2R) CH 3 -CH(CH 3)OCOOC 6 H 11 Cl-CH(CH 3)OCOOC 6 H 11 48 Cis-(lS,2R) CH 3 1-(2,6-dimethylcyclohexyl1-chloroethyl 2,6-dimethyl oxycarbonyloxy)ethyl cyclohexylcarbonate 49 Cis-RAC CH 3 -CH 2 CONEt 2 Cl-CH 2 CONEt 2 Cis-RAC CH 3 -CH 2 CONPh 2 1-CH 2 CONPh 2 51 Cis-RAC CH 3 -CH 2 CON[CH(CH 3Y2 Cl-CH 2 CON[CH(CH 3)212 52 Cis-RAC CH 3 -CH 2 CONHCH(CH 3)2 Cl-CH 2 CONHCH(CH 3)2 53 Cis-RAC CH 3 -CH 2 CON(CH 3)CH 2 CH 2 OH Cl-CH 2 CON(CH 3)CH 2 CH 2 OH 54 Cis-RAC CH 3 -CH 2 CON(CH 3)CH 2 CONH 2 Cl-CH 2 CON(CH 3)CH 2 CONH 2 Cis-RAC CH 3 -CH 2 CONnBU2 ClCH 2 CONnBu 2 56 Cis-RAC CH 3 -CH 2 CO-(l-piperidyl) Cl-CH 2 CO-(l-piperidyl) 57 Cis-RAC CH 3 -CH 2 CO-(l-morpholin) Cl-CH 2 CO-(l-morpholin) 66 Cis-RAC CH 3 4-methoxyphenylcarbonyloxy 4-methoxyphenylcarbonyloxy methyl methyl chloride - (continued) (continued) Comp. Stereoisomery 2 2 n. cpd. 3 R R R Hal cpd. 1 67 Cis-RAC CH 3 3-methoxyphenylcarbonyloxy- 3-methoxyphenylcarbonyloxy me thy 1 methyl chloride 68 Cis-RAC CH 3 -CH(CH 3)OCOCH(CH 2 CH 3)2 Cl-CH(CH 3)OCOCH(CH 2 CH 3)2 69 Cis-RAC CH 3 -CH 2 OCOC(CH 3)3 Cl-CH 2 OCOC(CH 3)3 hi Cis-RAC CH 2 CH 3 -CH 2 OCOCH(CH 2 CH 3)2 Cl-CH 2 OCOCH(CH 2 CH 3)2 C) 71 Trans-RAC CH 3 -CH(CH 3)OCOCH(CH 2 CH 3)2 Cl-CH(CH 3)OCOCH(CH 2 CH 3)2 72 Cis-RAC CH 2 CH 3 -CH 2 OCOCH(CH 2 CH 3)2 Cl-CH 2 OCOCH(CH 2 CH 3)2 73 Cis-RAC CH 3 -CH 2 OCOCH(CH 2 CH 3)2 Cl-CH 2 OCOCH(CH 2 CH 3)2 74 Cis-RAC CH 3 -CH 2 N(CH 3)C0Ph Cl-CH 2 N(CH 3)C0Ph Cis-RAC CH 3 -CH(CH 3)OCOOCH(CH 3)2 Cl-CH(CH 3)OCOOCH(CH 3)2 77 Cis-RAC CH 3 2-phenylbenzoyloxymethyl 2-phenylbenzoyloxymethyl chloride (continued) (continued) Comp. Base Cat. Solvent Reaction Reaction Solvent (PC 20 m.p. Physical st nd D n. 1 step Temperature time 2 step (1% EtOH)' ("C) state CT) 1 NEt 3 NaI DMF r. t. 20 h THF resin 2 DBU DMF r. t. 7 d THF resin 3 D BU DMF 55 6 d THF resin 4 NEt 3 - THF r.t. 2 h THF - resin DBU - DMF r.t. 4 d EtOAc +20.0o - resin W=1%,ETOH) - resin 6 DBU - DMF r.t. 3 d EtOAc - resin 7 DBU - DMF r.t. 3 d EtOAc - resin 8 NEt 3 NaI DMF r.t. 3 d THF 132 135 colourl.

crystals 9 NEt 3 NaI DMF r.t. 4 d THF 65-67 white solid DBU DMF r.t. 4 d EtOAc +7.4411 58-63 white solid (C=1%,ETOW - resin 11 DBU DMF r.t. 24 h CH 3 OH resin 12 DBU CH 3 CN 80 6 h THF resin 13 NEt 3 THP r.t. 12 h THF resin 1 (continue) - 1 (continued) - Comp. Base Cat. Solvent Reaction 1 st step Temperature (OC) Reaction Solvent 1.00 20 m.p. Physical nd D time 2 step (1% EtOH) Pc) state 14 NE t 3 - THF t. 12 h THF resin NEt 3 - THF r. t. 12 h THF resin 16 KOH - DMF r. t. 24 h THF 102-109 whitish solid 17 DBU - DMF r.t. 5 d EtOAc - resin 18 NEtiPr 2 - DMF r.t. 4 d EtOAc +14.011 resin (C=1%,ETOH) 19 NEt 3 NaI DMF r.t. 3 d THF -11.00 - resin NEt 3 NaI DMF r.t. 6 d THF - - resin 21 NEt 3 NaI DMF r.t. 24 h THP - 98-101 white solid 22 NEt 3 NaI DMF r.t. 24 h THF - 123-126 white solid 23 NEt 3 NaI DMF r.t. 20 h THF - 103-111 pale yellow solid 29 NEt 3 NaI DMF r.t. 2 d THF - - colourl liquid (continued) rli hi 1 (continued) Comp. Base Cat. Solvent Reaction Reaction Solvent 10(1 20 m.p. Physical st nd D n. step Temperature time 2 step (17, EtOH) PC) state PC) DBU DMF t. 3 d EtOAc +14.911 79-81 white (C=1%,ETOH) solid 31 DBU DMF r.t. 7 d EtOAc - - resin 32 NEt 3 NaI DMF r.t. 3 d THF - 128-132 colourl.

crystals 33 DBU - DMF r.t. 4 d EtOAc - 49-50 white solid 34 DBU - DMF r.t. 20 h THF - - resin DBU - DMF r.t. 20 h THF - 78-84 solid 36 DBU - DMF r.t. 18 h EtOAc +24.511 55-56 white (C=0.5%,ETOH) solid 37 DBU - DMF r.t. 18 h EtOAc +22.311 75-78 white (C=1.05%,ETOH) solid 38 NEt 3 - THF r.t. 12 h THF - resin 39 NEt 3 - THF r.t. 12 h THF - resin NEt 3 - THF r.t. 12 h THF - - resin 41 DBU - DMF r.t. 2 d EtOAc +14.111 - resin (C=1%,ETOH) (continued) (continued) Comp. Base Cat. Solvent Reaction Reaction Solvent 20 m.p. Physical st nd D n. step Temperature time 2 step (1% EtOH) (,,C) state ( OC) 42 DBU DMF t. 2 d EtOAc +16.111 resin (C=1%,ETOH) 43 DBU DMF r. t. 3 d EtOAc +10.311 resin (C=1%,ETOH) 44 NEt 3 NaI DMF r.t. 3 d THF +11.90 resin (C=1%,ETOW DBU DMF r.t. 3 d THF +8.80 resin (C=1%,ETOH) 46 NEt 3 NaI DMF r.t. 3 d THF +9.011 resin (C=1%,ETOH) 47 NEt 3 NaI DMF r.t. 3 d THF +7.711 resin (C=17o,ETOH) 48 NEt 3 NaI DMF r.t. 3 d THF +7.611 45-53 white (C=1%,ETOH) solid 49 NEt 3 NaI DMF r.t. 24 h THF 123-124 white NEt NaI DMF r.t. 24 h THF solid 3 133-135 white solid 1 (continued) - (continued) Comp. Base Cat. Solvent Reaction Reaction Solvent [Ofl 20 m.p. Physical st nd D n. 1 step Temperature time 2 step (1% EtOH)' (OC) state Pc) 51 NEt 3 NaI DMF r.t. 24 h THF - 5859 white solid 52 NEt 3 NaI DMF r.t. 24 h THF - 76 white 53 NEt 3 NaI DMF r.t. 24 h THF - solid 54 NEt NaI DMF r.t. 24 h THP - - waxy 3 84 85 white NEt NaI DMF r.t. 24 h solid 3 THF - waxy 56 NEt 3 NaI DMF r.t. 24 d THF 49 white -57 NEt NaI DMF r.t. 24 h THF solid 3 41-45 white solid 66 DBU DMF r.t. 4 d EtOAc 62-64 white 67 DBU DMF r.t. 4 d EtOAc 49-51 wsholied solid 68 DBU CH 3 CN 80 6 h THF resin (continued) - r\j Ln (continued) Comp. Base Cat. Solvent Reaction Reaction Solvent WI 20 m.p. Physical st 1 nd D n. 1 step Temperature time 2 step (1% EtOH)' (OC) state PC) 69 DBU - DMF r.t. 4 d THF - - resin DBU DMF r.t..4 d THF - - resin 71 DBU - CH 3 CN 80 6 h THF - - resin 72 DBU CH 3 CN 80 6 h THF - - liquid 73 DBU - DMF r.t. 4 d EtOAc - - resin 74 DBU - DMF r.t. 3 d EtOAc - - resin NEt 3 NaI DMF r.t. 3 d THF - resin 77 DBU DMF r.t. 4 d EtOAc - 60 64 white solid (continued) Table 3

Preparation of compounds of formula 1 according to scheme II (R2 = H) Comp. Stereoisomery 2 n. cpd. 4 R R R Hal cpd. 1 24 Cis-(lS,2R) CH 3 -COC (CH 3)3 ClCOC(CH 3)3 Cis-(lS,2R) CH 3 -CO-adamantyl 1-adamantancarbonyl chloride 26 Cis-(lS,2R) CH 3,4,5-trimethoxybenzoyl 3,4,5-trimethoxybenzoyl 3 chloride 27 Cis-(lS,2R) CH 3 pyridin-3-carbonyl nicotinoyl chloride 28 Cis-(lS,2R) CH 3 -COO(CH2)3CH 3 CICOO(CH 2)3CH3 58 Cis-(lS,2R) CH 3 -COCH 3 ClCOOCH 3 59 Cis-(lS,2R) CH 3 -COCH(CH 2 CH 3)2 CICOCH(CH 2 CH 3)2 Cis-(lS,2R) CH 3 -CO(CH 2)10 CH 3 CI-CO(CH 2)10 CH 3 61 Cis-(1S,2R) CH 3 -COPh Cl-COPh 62 Cis-(lS,2R) CH 3 2-chlorobenzoyl 2-chlorobenzoyl chloride 63 Cis-(lS,2R) CH 3 2-nitrobenzoyl 2-nitrobenzoyl chloride 64 Cis-(lS,2R) CH 3 -COOCH 2 CH 3 Cl-COOCH 2 CH 3 Cis-(lS,2R) CH 3 -COOCH 2 Ph Cl-COOCH 2Ph 76 Trans-RAC CH 2 CH 3 -COPh Cl-COPh t.

(continued) (continued) Comp.. Base Reaction Reaction Reaction Crystalliza- 1OU p 20 m.p. Physical n. Solvent. Temperature time tion soivent PC) state PC) 1 24 NaOH H 2 0/THF 0 301 EtOAc +19.811 138-140 white crystals DBU DMF r. t. 3 h Et 2 0 -4.90 153-155 white solid 26 NaOH H 2 0/THF 0 451 THF -2.9 78-84 white solid 27 NaH DMF r.t. 12 h Et0AclEt 2 0 +38.6c, 38-101 yellow solid 28 NaOH H 2 0/THF 0 3 h +10.311 - white 11 resin 58 NaOH H 2 0/THF 0 301 EtOAc -10.311 122-124 crystals 59 NaOH H 2 0/THF 0 301 EtOAc -22.511 128-130 crystals NaOH H 2 0/THF 0 301 EtOAc +18.10 113-114.50 crystals 61 NaOH H 2 0/THF 0 300 - 70-800 amorphous solid 62 NaOH H 2 0/THF 0 301 62-66 amorphous solid (continued) (continued) A 20 Comp. Base Reaction Reaction Reaction Crystalliza- W]D m.p. Physical n. Solvent Temperature time tion solvent PC) state PC) 63 NaOH H 2 0/THF 0 301 62-700 amorphous solid 64 NaOH H 2 0/THF 0 3 h -1.90 - yellow solid NaOH H 2 01THF 0 3 h -0.80 55-63 amorphous solid 76 NaOH H 0/THF 0 3 h - 148-150 white 2 crystals

Claims

1 1. A compound of formula 1 R 3 NH R CHi", 0 11 Q 2 0 COOR 1 wherein R 1 is c i-c 4 alkyl; R 2 is H; C i-c 12 alkyl; C 3-C6 cycloalkyl; phenyl; C 1-C 4 alkoxYMe thyl; 2-te trahydrof urylme thyl; 2-di (C 1-C 4 alkyl)aminoethyl; -CH(R 4)OCOR 5 -CH(R 4)COR 6; N-methyl is benzamidylmethyl; R 3 is hydrogen; (C 1-C6 alkoxy)carbonyl; benzyloxycar banyl; (C i-c 12 alkyl)carbonyl; adamantylcarbonyl; phenylcarbonyl optionally substituted by 1 to 3 substi tuents selected from Cl, NO 2 and OCH 3; 3-pyridyl-car bonyl; 4 is hydrogen; C 1-C 6 alkyl; is c 1-C 12 alkyl; adamantyl; -(CH 2)0-2 c 4-C6 cyclo- alkyl; (C 1-C 6 alkyl) -COOH; (C 1-C6 alkyl)-CONR 4; 2-, 3 or 4-piperidinyl; 2-, 3- or 4 -pip eridin-l-benzoyl; phenyl optionally substituted by 1 to 3 substituents selected from R 4 ' OCH 31 OHI OCOO(Ci-c 4 alkyl), Cl; cis and trans 2-[[[2-(hydroxyamino)-2-oxoethyll(C 1-C 4 alkyl) amino] carbonyl]cyclohexyl; C i-c 6 alkoxy; C CC6 cy cloalkoxy optionally substituted by 1 to 2 substituents selected from R 4; biphenyl; R 6 is -NR 7 R 8; 1-piperidinyl; 1-morpholinyl; 31 R 7 and R 8, which are the same or different, are H; c 1-C 6 alkyl; phenyl; C,-C4 hydroxyalkyl; CH.CON(R 4); CH(COOH)CH 2 Ph; OH; with the provisos that:

R 2 and R 3 are not contemporaneously H; when R' is methyl and R 3 is hydrogen, R 2 is different from methyl and from acetyloxymethyl; when R 1 is ethyl and R 2 is hydrogen, R 3 is different from acetyl; - when R 1 is methyl, R 2 and R 3 are not contemporane- oulsy CH 3; including a non-toxic salt thereof, single enantiomers and/or diastereoisomers.

2. A compound according to claim 1, wherein R is methyl or ethyl; R 2 is hydrogen, C 3-C12 alkyl; C 3-C6 cycloalkyl; phenyl; C 1-C 4 alkoxymethyl; 2-tetrahydrofurylmethyl; 2-di(C 1-C 4 alkyl)aminoethyl; N-methylbenzam.idylmethyl; CH(R 4) OCOR 5; CH (R 4) COR 6; R 3 is hydrogen, (C 1-C 6 alkoxy)carbonyl; benzyloxycarbonyl; (C 1-C 12 alkyl)carbonyl; adamantylcarbonyl; phenylcarbonyl op- tionally substituted by 1 to 3 substituents selected from Cl, NO 2 and OCH 3; R 4 is hydrogen and methyl; R 5 is c 4-C12 alkyl; -(CH 2)0-2-C4-C6 cycloalkyl; (C 1-C6 alkyl) -COOH; (C 1-C 6 alkyl)-CONR 4; 2-, 3- or 4- piperidinyl; 2-, 3- or 4-piperidyn-l-benzoyl; diphenyl; phenyl optionally substituted by 1 to 3 substituents selected from R 4, OCH 31 OH, OCOO(Cl- C4 alkyl), Cl, cis or trans 2-[[[2-(hydroxyamino)-2-oxoethyl]-(C 1-C 4 alkyl)amino]carbonyllcyclohexyl; C 1-C 6 alkoxy C 1-C 6 cycloalkoxy optionally subtituted by 1 to 2 substituents selected from R 4; R 6 is as above defined, with the proviso that R 2 and R 3 are not contemporaneously 32 hydrogen.

3. A compound. according to claim 1, wherein R 3 is hydrogen and R 2 is C 3C12 alkyl, preferably C 6-C12 alkyl; 2-tetrahydrofurylmethyl, methoxymethyl, 2-diethylamino- ethyl or a group of formula CH(R 4)OCOR 5, wherein R 4 is hydrogen or methyl and R 5 is c 4-C12 alkyl; - (CH 2)0-1 cyclohexyl, (C 3-C4 alkyl)- COOH, (C 3-C4 alkyl)-CONEt 2; piperidinyl; piDeridin-lbenzoyl; adamantyl; N-methyl benzamidyl,nethyl; phenyl optionally substituted by 1 to 3 substituents selected from R 4 p OCH 3, 0HP OCOO(C 1-C 4 alkyl), Cl; diphenyl.

4. A Compound according to claim 1, wherein R 3 is hydrogen and IR 2 is a CH(R 4)COR 6 group, wherein R 4 is hydrogen and R 6 i s -NR 7 R 8 wherein R 7 and R 8, the same or different, are hydrogen; c 1-C6 alkyl; C 1-C 4 hydroxyalkyl; CH 2 CONH2; CH(COOH)CH 2 PhOH; or R 7 and R 8 J. taken together with N atom which they are bound to form a 1-piperidinyl or 1morpholinyl ring.

5. A compound according to claim 1, wherein R 3 is hy drogen, R 2 is a group of formula CH(R 4)OCOR 5 wherein R 4 is hydrogen or methyl and R 5 is a C 1-C 6 alkoxy; C 4-C6 cycloalkoxy optionally substituted by 1 to 2 substi tuents selected from R 4.

6. A compound according to claim 1, wherein R 2 is hydrogen and R 3 is (C 1-C 4 alkoxy)carbonyl; benzyloxycarbonyl; (C 1-C 12 alkyl)carbonyl; phenylcarbonyl, optionally substituted by 1 to 3 substituents selected from Cl, NO 21 OCH 3; adamantylcarbonyl; 3-piridylcarbonyl.

7. A compound as claimed in any one of claims 1 to 6 substantially as herein described or exemplified in any example.

8. A process for the preparation of a compound of any one of claims 1-to 7, Cotprising reacting a compound of formula 2 33 \W R 1 1 1 N 1 6 000H 2 wherein R1 is as above defined with a halo-derivative of formula R2Hal, wherein Hal is chlorine, bromine or iodine and R2 is as defined in claim 1, followed by removal of the benzylic group.

9. A process for the preparation of a compound as claimed in any one of claims 1-7, comprising reacting a compound of formula 4 R1 0: C 0-K N% C__.ooQ 11 0 COCH 4 wherein R' is as def ined in claim 1, with a compound of formula R3Hal, wherein Hal is chlorine, bromine, iodine and R3 is as defined in claim 1.

10. A process as claimed in claim 8 or 9 substantially as herein described or exemplified in any example.

11. A pharmaceutical composition containing at least one compound as claimed in any one of claims 1-7 as an active ingredient.

12. Use of a compound as claimed in any one of claims 1 to 7 in the preparation of a medicament for use in treating hypertensive disease or heart failure, diabetic nephropathies, cardiac infarct, cardiac hypertrophy, vascular proliferation Pr CL disease of the Central Nervous System.