FR2706897A1 - - Google Patents

Abstract

The invention relates to certain derivatives of cis- and trans-2- [[[2- (hydroxyamino) -2-oxoethyl] alkylamino] carbonyl] -cyclohexanecarboxylic acids having the formula: (CF DRAWING IN BOPI) where R1 = alkyl, R2 is, for example, an alkyl, cycloalkyl, phenyl, alkoxymethyl, etc ..., and R3 is, for example, H or an alkoxycarbonyl, benzyloxycarbonyl, alkylcarbonyl, phenylcarbonyl, etc ... group, as well as their enantiomers which are endowed with antihypertensive activity, their methods of preparation and their use in pharmaceutical compositions. Application to the pharmaceutical field.

Description

The present invention relates to certain derivatives

  of acid and trans-2 - [[[2- (hydroxyamino) -2-oxoethyl] -

  alkylamino] carbonyl] cyclohexanecarboxylic acids and their enantiomers which are endowed with antihypertensive activity, their method of preparation and their use in

pharmaceutical compositions.

  The compounds of the invention are represented by the general formula 1:

R3O \ R1

NH T

O COOR2

  ! wherein R 'is C 1 -C 4 alkyl; R2 is H, C1-C12alkyl, C3-C6cycloalkyl, phenyl, (C1-C4alkoxy) methyl, 2-tetrahydrofurylmethyl, 2-di (C1-C4alkyl) -C4) aminoethyl, -CH (R4) OCOR5, -CH (R4) COR6 or N-methylbenzamidylmethyl group; R3 is hydrogen, (C1-C6) alkoxycarbonyl, benzyloxycarbonyl, (C1-C12) alkylcarbonyl, adamantylcarbonyl, phenylcarbonyl optionally substituted with 1 to 320 substituents selected from Cl, NO2 and OCH3, or a 3-pyridylcarbonyl group; R4 is hydrogen or C1-C6 alkyl; Rs is a C1-C12 alkyl group, an adamantyl group, a - (CH2) 0-2- (C4-C4) cycloalkyl group, a (C1-C6) alkyl group - COOH, a (C1-C4) alkyl group; C1-C6) -CONR4, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-piperidine-1-benzoyl, phenyl optionally substituted with 1 to 3 substituents selected from R4, OCH3 , OH, OCOO (C1-C4) alkyl and Cl, a -3- or trans-2 - [[[2- (hydroxyamino) -2-oxoethyl] (C1-C4 alkyl) amino] carbonyl] cyclohexyl group, a C 1 -C 6 alkoxy group, a C 4 -C 6 cycloalkoxy group optionally substituted with

  1 or 2 substituents selected from R4, or a diphenyl-

  yl; R6 is -NR7R8, a 1-piperidinyl group or a 1-morpholinyl group; R7 and R8, which are the same or different, are each H, C1-C6 alkyl, phenyl, C1-C4 hydroxyalkyl, CH2CON (R4) 2, CH (COOH) CH2Ph or OH, and their combinations; with the following conditions: - R2 and R3 are not simultaneously H; if R 'is a methyl group and R3 is hydrogen, then R2 is other than a methyl group or an acetyloxymethyl group; if R1 is an ethyl group and R2 is hydrogen, then R3 is other than an acetyl group; - if RI is a methyl group, then R2 and R3 are not

not simultaneously CH3.

  The invention also includes non-toxic salts, isolated enantiomers or diastereoisomers and mixtures

of compounds 1 between them.

  Compounds excluded by the foregoing conditions are known from U.S. N 5 095 137 o their favorable pharmaceutical properties have, however,

not described or acknowledged.

  In the compounds of Formula I, R 'is preferably a methyl or ethyl group; R2 is preferably hydrogen, C3-C12 alkyl, C3-C6 cycloalkyl, phenyl, (C1-C4) alkoxy methyl, 2-tetrahydrofurylmethyl, 2- di (C 1 -C 4) alkylaminoethyl, CH (R 4) OCOR 5 or

  CH (R4) COR6; R 3 is preferably hydrogen, a C 1 -C 6 alkoxycarbonyl group, a benzyloxycarbonyl group, a C 1 -C 12 alkylcarbonyl group, an adamantyl group,

  carbonyl or a phenylcarbonyl group optionally substituted with 1 to 3 substituents selected from Cl, NO2 and OCH3; R4 is preferably hydrogen or a methyl group; Rs is preferably a C4-C12 alkyl group, a - (CH2) 12-C4-C6 cycloalkyl group, a (C1-C6) alkyl -COOH group, a (C1-C6) alkyl group -CONR42, a 2-, 3- or 4-piperidinyl group, a 2-, 3- or 4-piperidine-1-benzoyl group, a phenyl group optionally substituted with 1 to 3 substituents selected from R4, OCH3, OH, OCOO (alkyl);

  C1-C1) and C1, a cis- or trans-2- [[[2- (hydroxyamino)] group;

  2-oxoethyl] - (C 1 -C 4) alkylamino] carbonyl] cyclohexyl, C 1 -C 6 alkoxy or C 4 -C 6 cycloalkoxy optionally substituted with 1 or 2 substituents selected from R 4; Re is as defined above; with the proviso that R2 and R3 are not simultaneously

Hydrogen.

  Preferred classes of the compounds of Formula I are those wherein A) R3 is hydrogen and R2 is a C3-C12 alkyl group,

  preferably C6-C12 alkyl; a 2-tetrahydrofuryl group

  methyl, a methoxymethyl group, a 2-

  diethylaminoethyl or a group of the formula CH (R4) OCOR5 wherein R4 is hydrogen or a methyl group and R5 is a C4-C12 alkyl group; (CH 2) 0-cyclohexyl, (C 3 -C 4) alkyl-COOH, (C 3 -C 4) alkyl-CONEt 2; piperidinyl;

  piperidine-l-benzoyl; adamantyl; N-méthylbenzamidyl-

  methyl; phenyl optionally substituted with 1 to 3 substituents selected from R4, OCH3, OH, OCOO (C1-C4) alkyl and Cl; or diphenyl; B) R3 is hydrogen and R2 is a group of formula CH (R4) COR6 wherein R4 is hydrogen and Re is -NR7R8 wherein R7 and R8, which are the same or different, are each hydrogen; a C1-C6 alkyl group; phenyl, diphenyl; C1-C4 hydroxyalkyl; CH2CONH2; CH (COOH) CH 2 Ph; or OH; or R7 and R8, taken together with the nitrogen atom to which they are attached, form a 1-piperidinyl or 1-morpholinyl ring; C) R3 is hydrogen and R2 is a group of the formula CH (R4) OCORs wherein R4 is hydrogen or methyl and R5 is C1-C6 alkoxy; a C4-C6 cycloalkoxy group optionally substituted with 1 or 2 substituents selected from R4; D) R2 is hydrogen and R3 is (C1-C4) alkoxycarbonyl; a benzyloxycarbonyl group; a C1-C12 alkylcarbonyl group; a phenylcarbonyl group optionally substituted with 1 to 3 substituents selected from Cl, NO2 and OCH3; an adamantylcarbonyl group; a

3-pyridylcarbonyl group.

  The starting compounds, namely cis-2 - [[[2-

  (hydroxyamino) -2-oxoethyllmethylamino] carbonyl] -

  cyclohexanecarboxylic acid I and trans-2 - [[[2-

  (Hydroxyamino) -2-oxoethyl] ethylamino] carbonyl] cyclohexanecarboxylic acid II, and in particular their biologically active stereoisomers, respectively (1S, 2R) - of compound I and (1R, 2R) - of compound II, known from FIG. Italian Patent No. 1,224,627 and the US Patent N 5,095,137, exert a remarkable inhibitory activity of ACE (

  angiotensin) and represent a novel structure of ACE inhibitors that is not an amino acid structure, thus emerging as potential new therapeutic agents for the treatment of hypertension.

  The compounds of Formula 1 have improved properties which make them particularly useful for the treatment of disorders due to hypertension and heart failure, diabetic nephropathies, myocardial infarction, cardiac hypertrophy, Vascular proliferation and diseases of the central nervous system. For the intended therapeutic applications, the compounds of the invention are formulated into conventional pharmaceutical preparations suitable for oral, parenteral or transdermal administration, using known methods and excipients, described for example in

  "Remington's Pharmaceutical Sciences Handbook", Mack Pub.

  Co., NY, USA, 17th ed. The daily dose depends on several factors such as the nature and severity of the disease to be treated, the condition of the patient (weight, sex, age), but is generally between 1 and 500 mg, possibly

  divided into several administrations.

  The processes, which are another subject of the invention, for the preparation of the compounds of Formula 1 comprise the conversion, according to Scheme I, of the benzylated product 2 to the corresponding derivative ester 3, by reaction with an appropriate halogenated compound ( 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 100 C, preferably at the

ambient temperature.

  The starting material 2 is already known (U.S. Patent No. 5,095,137) and the halogenated compounds represented by R2Hal are commercially available products or can be prepared by known methods. The product 3 thus obtained, suitably purified, subjected to hydrogenolysis of the benzyl protecting group by reaction with hydrogen in the presence of a suitable catalyst, dissolved in an organic solvent such as THF or ethyl acetate, gives the compounds 1 of the invention wherein R3 = H.

6 2706897

SCHEME I

  OCH2Ph OPR2Halh B CH \ NHux R o \ NCH2 R

00 O COOR2

2 3

H2, Pd / C HO \ NX TO 1 i

SCHEMA II

  mpo Pl dlo compound 4, alreadyHco, avcBs c RI

\ N I I IOO

  C2 N suitable such as an aqueous solution of NaOH, Na0 or DBU,

  at a temperature of 0 to 500C, preferably 0 to 300C.

  The aforementioned R3Hal compounds, i.e., acyl halides or haloformates, are commercial products or are prepared by known methods. The compounds of the invention have evaluated the proportion of in vivo compotests designed to detect Ha, in Hal is animals,

  Preferably, the inhibitory activity of ECA which expresses antihypertensive properties such as, as well as NaOH, NaH or DBUcomparer a temperature of 0 to 50 C, preferably 0 to 300C.

  The above-mentioned R3Hal compounds, i.e., acyl halides or haloformates, are commercially available products or are prepared by known methods. The compounds of the invention were evaluated by in vivo tests designed to detect, in animals, the ACE inhibitory activity which expresses their potential antihypertensive properties, as well as to compare their biological properties with those of the compounds.

  disclosed in the U.S. Patent. N 5 095 137.

  As is already known, ACE inhibitors exert their antihypertensive activity by inhibiting the ACE-catalyzed biosynthesis of angiotensin II, a potent endogenous vasoconstrictor, from its precursor, angiotensin I. The inhibitory action is due to the ability of these molecules to bind, by specific functional groups, to the active site of the enzyme in competition with angiotensin I. The enzymatic activity of ACE inhibitors is determined directly to the enzyme by in vitro tests, whereas the ACE inhibitory action is evaluated in vivo by measuring the decrease in pressure elevation induced in animals by repeated administrations of angiotensin I. The invention investigated in experimental animals demonstrated ECA inhibitory activity both after intravenous administration and after oral administration. Table I reproduces the pharmacological results obtained for a wide selection of the most remarkable compounds. From the values given in the Table, it appears that the compounds of the invention also have a very good bioavailability after oral administration, as evidenced by the low values of DE50 po and DE50 iv. The compounds of the invention have been shown inactive in the in vitro CAE inhibition test, presumably because of the chemical transformations affecting their "binding" groups in the US Patent In addition, certain compounds modified at the carboxyl or hydroxamic moiety (ie the compounds of Examples 10, 12 to 16, 42 and 43 of said U.S. Patent) are also disclosed. These compounds were studied only to the extent that the effects of chemical transformations on affinity for ACE were concerned, but in vivo oral ACE inhibitory activity was not determined. These compounds have now also been studied after oral administration and compared to the compounds of the present invention; the results show that the compounds "modified"

  previously described do not have a better bioavailability than their precursors after oral administration and can not be compared in this respect with the compounds of the present invention.

  TABLE I - Effect on angiotensin I-induced pressure response in the rat: (ED50), time to maximal effect (Tmax) and duration (T1 / 2) of the compounds administered by the intravenous (iv) routes, intraduodenal (id) and oral (po)

i.v. i.d. PO

Example

  N DEs0a) Tmaxc T1 / 2d DE50 Tmax T1 / 2 DE50b) Tmax T1 / 2 jmol / kg min min umol / kg min min mol / kg 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 20-30 70

0.57 1 60 1.2 16-21 60 1.5 30-

  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

TABLE I (continued)

i.v. i.d. PO

  Example 1 N DE50a) Tmaxc T1 / 2d DE50 Tmax T1 / 2 DE50b) Tmax T1 / 2 mol / kg min min imol / kg min min imol / kg 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

34.44C

he 2,2 he

33 4.8

36 6.4 20

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

TABLE I (continued)

i.v. i.d. PO

  Example N DE50a) Tmaxc T1 / 2 DE50 Tmax T1 / 2 DE50b Tmax T1 / 2 Jmol / kg min min gmol / kg min min Ammol / kg 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 described in the cited examples of the US Patent N 5 095 137

  a) Pharmacological method: i.v. and i.d.

  The animals are anesthetized with ethyl urethane (1.5 g / kg intramuscularly). The right femoral vein and left jugular vein are equipped with cannulas for the administration of pentolinium tartrate (0.1 mg / kg / min), angiotensin I and the test compound. A catheter is inserted into the left carotid artery and connected to a Benthley Trantec 800 pressure transducer (U. Basil). After 30 minutes, with equilibrium achieved, angiotensin I (310 mg / kg) is injected at 5 minute intervals until

  three reproducible responses were obtained.

  One minute before the next administration of angiotensin I, the compounds to be examined are administered intravenously or intraduodenally. Angiotensin I injections are repeated until the pressure response returns to baseline. An animal is used to test each dose of each compound. The values of ED50 are calculated from the

  peak of inhibitory activity. b) Pharmacological method: p.o.

  Animals subjected to fasting for 16 hours are moderately anesthetized with ethyl ether to introduce cannulas into the left jugular vein and the left carotid artery. The other ends of the cannulas are routed under the skin and externalized on the neck. The rats are placed in individual cages and the mean blood pressure is measured as previously described. After one hour, with equilibrium achieved, angiotensin I (310 mg / kg) is injected at 10-minute intervals until three responses are obtained.

  reproducible were obtained.

  Ten minutes before the next administration of angiotensin I, the compounds to be examined are administered orally by a gastric tube. Angiotensin I injections are repeated every 10 minutes for 2 hours after administration of the drug. c) Time of onset of maximal effect, in minutes after administration (1-6 means the interval between the first and sixth minutes). The present invention is further illustrated by

  the following non-limiting examples.

  EXAMPLE 1 General procedure for the preparation of compounds of Formula 1 according to Scheme I. 1st step: 8.6 mmol of halogenated compound (R2-Hal) in 10 ml of solvent are added to a mixture of 8.6 mmol of the compound starting point 2, having the appropriate stereoisomerism, 8.6 mmol base, optionally in the presence of 1.72 mmol

NaI as a catalyst.

  The reaction mixture is stirred for the duration and

  at the temperature indicated in Table 2.

  The reaction mixture is then evaporated to dryness and the residue is added with ethyl acetate and a

saturated solution of NaCl.

  After separation of the phases, the organic phase is washed with 5% aqueous HCl, a saturated aqueous solution of

  NaHCO3, a 5 W solution of Na2S203 (in the case where Na1 is used as a catalyst), water and finally dried over MgSO4.

  After removal of the solvent by evaporation under vacuum, the crude product 3 is used as it is in the next step, otherwise it is purified by flash chromatography on a silica gel column. Step 2: A solution of 2.1 mmol of product 3 in 30 ml of the appropriate solvent is hydrogenated under pressure

  ambient and at room temperature in the presence of 10 W by weight of catalyst at 10 W Pd / C. After the theoretical absorption of hydrogen, the suspension is filtered, concentrated and evaporated to dryness in vacuo.

  The products listed in Table 2 below, obtained according to the procedure described above, were pure in HPLC and TLC analysis; in addition, the 1 H NMR analysis confirmed the expected structure and the elemental analysis (C, H, N) was in agreement with the

theoretical values.

EXAMPLE 2

  General procedure for the preparation of compounds of

Formula 1 according to Scheme II.

  Method A (Compounds 24, 26, 28, 58 to 65 and 76) 22.5 mmol of 1M NaOH are added to an aqueous solution, cooled to 0 ° C., of 10.7 mmol of the starting compound 4 and added dropwise to the resulting solution ml of a solution of the halo compound R3-Hal in THF. The mixture is stirred at 0 ° C for the time indicated in Table 3 below, then is acidified, maintaining the same temperature, with 2% HCl and extracted with methylene chloride (4 × 40 ml). The organic phases are combined and washed with water (10 ml), dried over

  MgSO 4 and evaporated under reduced pressure.

  Method B (Compound 25) 14.2 mmol of DBU was added to a solution of 7 mmol of compound 4 in 20 ml of DMF and a solution of water was added dropwise at room temperature.

  5.7 mmol of halogenated compound (see Table 3) in 10 ml of DMF.

  The reaction mixture is stirred at room temperature for 3 hours, after which the solvent is removed by evaporation and the residue, added

  of methylene chloride, is washed with 5% HCl and water, dried over MgSO 4 and evaporated to dryness.

  Method C (Compound 27) 16.8 mmol of NaH (60% suspension in paraffin) are added portionwise to a solution of 8.0 mmol of compound 4 in 30 ml of DMF and then a suspension is added dropwise. 8.0 mmol of nicotinoyl chloride hydrochloride in 20 ml of DMF. The reaction mixture is

  stirred overnight at room temperature, then diluted with ethyl acetate, washed with saturated aqueous NaCl solution and water, dried over MgSO 4 and evaporated to dryness.

  The crude products obtained according to the methods A, B or C, are already pure in some cases, as shown by HPLC and TLC; in other cases, they are purified by crystallization in appropriate solvents or solvent mixtures. For all the products listed in Table 3, the NMR analysis of 'H' confirms the expected structure and

  elemental analysis was in agreement (0.4%).

TABLE 2

  Preparation of compounds of formula 1 according to scheme I (R3 = H) Stereoisomeria Compound Compound 2 R1 R2 R2Hal N Compound 1 1 Cis-RAC CH3 CH20CH3 CCH OCH

-CH20 C13CH2OCH3

  Cis (1S, 2R) CH3-CH2CH2NEt2 ClCH2CH2NEt2 Cis-RAC CH3 2-tetrahydrofurylmethyl. bromofurfurol 4 Cis-RAC CH3 -CH2OCOCH3 I-CH2OCOCH3 Cis- (IS1j2R) CH3-CH2OCOC (CH3) 3 C1-CH2OCOC (CH3) 3 6 Ci-s-RAC CH3-CH2OCO (CH2) 3COOH Cl-CH2OCQO (CH2) 3COOCH2Ph 7 Cis- (1S, 2R) CH3C1-CH2OCO (CH2) 3CONEt2C1-CH2OCO (CH2) 3CONEt2

  8 Cis-RAC CH3 piperidine4-carbonyloxymethyl-N-benzoyloxycarbonyl-

  chloromethyl piperidine-4-carboxylate

  Cis- (1S, 2R) CH3 N-benzoylpiperidint3-carbonyl-N-benzoylpiperidine-3-

  chloromethyl oxyethyl-carboxylate

  3,4,5-trimethoxybenzoyloxymethyl chloride 3,4,5-trimethoxy-

benzoyloxymethyl

  Cis (1S, 2R) CH adamantoyloxymethyl-adamantoyloxy chloride

  Methyl Cis- (1S, 2R) CH-CH (CH 3) OCOCH (CH 2 CH 3) 2 Cl-CH (CH 3) OCOCH (CH 2 CH 3) 2

3 3 2 3 2 3

  TABLE 2 (cont.) Stereoisomeria Compound Compound R1 R2 R2Hal N Compound 1 13 Cis-RAC CH3-CH (CH3) OCOC (CH3) 3 I-CH <CH3) OCOC (CH3) 3 14 Trans-RAC CH2CH3-CH (CH3 ) OCOC (CH3) 3 I- CH (CH3) OCOC (CH3) 3

  Trans-RAC CH2CH3 1- (cyclohexylacetyloxy) ethyl acetate of 1-iodoethyl

  cyclohexyl 16 Cis-RAC CH3 1 with R = CH-, R = CH3 3 with R = CH3, R = CH2Cl 17 Cis- (LS, 2R) CH3-CH20COOCH3 CICH2OCOOCH3 18 Cis- (IS, 2R) CH3 CH20COOCH2C (CH3) C1CH2OCOOCH2C (CH3) 3 C- (1S, 2R) CH3-CH (CH3) OCOOCH2CH3 ClCH (CH3) OCOOCH2CH3 Trans- (1S, 2R) CH2CH3-CH (CH3) OCOOCH (CH3) 2 C1-CH (CH3IOCOOCH ( CH3) 21 Cis-RAC CH3-CH2CON (CH3) 2 Cl-CH2CON (CH3) 2 22 Cis-RAC CH3-CH2COOH Br-CH2COOCH2Ph 23 Cis-RAC CH3-CH2 CONCH (CH2Ph) COOH Br-CH2 CONCH (CH2Ph) COOCH2 Ph 29 Cis- (LS, 2R) CH3 (CH2) 11-CH3 Br- (CH2) ll-CH3

  Cis- (1S, 2R) CH 3 -CH 2 OCO (CH 2 CH 3) 10-undecenoyloxy chloride

  Methyl 31 Cis-RAC CH-CH2OCO (CH2) 4COOH C1-CH2OCO (CH2) 4COOCH2Ph

3 2 24, 24

  TABLE 2 (continued) Stereoisomerism Compound Compound 2 R1 R2 R2Hal N Compound 1

  32 Cis-RAC CH3 piperidint3-carbonyloxy-N-benzoyloxycarbonylpiperidine-

  chloromethyl methyl-3-carboxylate 33 Cis-RAC CH3-CH2OCOPh Cl-CH20COPh

  Cis-1 S, 2R) CH3 3,5-ditert-butyl-4-hydroxy-3,5-ditert-butyl-4-hydroxychloride

  benzoyloxy methyl-hydroxybenzoyloxymethyl Cis- (1S, 2R) CH 3,5-dimethoxy-4-ethoxycarboxylic chloride 3,5-dimethoxy-4-HO-bonyloxy methyl ethoxycarbonyloxymethyl

  36 Cis- (1S, 2R) 2,6-dimethylbenzoyloxy 2,6-dimethyl-

m3thyl. benzoyloxymethyl

  37 Cis - {(1S, 2R) 2,6-Dichlorobenzoyloxy 2,6-dichlorobenzoyl chloride

  ## STR4 ## ## ## STR1 ## Cis (IS, 2R) CH3-CH2-OCOOCH (CH3) 2C1-CH2OCOOCH (CH3) 2 Cis- (CH3) CHOCOCH2Cl3 Cl-CH2ClCOOCE2CH3 1S, 2R) CH3-C (CH) OCOCCHC-CH (CH3)) OCOOCH (CH3)

C-HC3) OOCHC3) 23 2

  TABLE 2 (continued) Stereoisomerism Compound Compound Z R1 R2 R2Hal N Compound 1 44 Cis (LS, 2R) CH3-CH (CH3) OCO (CH2) 3CH3 Cl-CH (CH3) OCOO (CH2> 3CH3 C18 (St2R) CH 3 -CH (CH 3) OCOOC (CH 3) 3 Cl-CH (CH 3) OCOOC (CH 3) 3 Cis- (1 S, 2R) CH 3 -CH (CH 3) CO CO 2 CH 2 C (Ct 3) 3 C1-CH (CH 3) OCOOCH 2 C (CH 3) > 3 47 Cis- (1S, 2R) CH3-CH (CH3) OCCOOC6H1 CI-CE (CH3) OCOOC6 H11

  48 Cis- (1S, 2R) CH 1- (2,6-dimethylcyclohexyl)

2,6-dimethylcyclohexyl

  oxycarbonyloxy) ethyl-1-chloroethyl carbonate Cis-RAC CH3-CH2CONEt2 C1-CH2CONEt2 Cis-RAC CH3 -CR2CONPh2 1-CH2CONPh2 Cis-RAC CH3-CH2CON [CH (CH 3) 22 C1-CH2CON [CH (CH3) 2] 2 Cis-RAC CH3 -CH2CONECH (CH3) 2 CL-CH2CONHCH (CH3) 2 53 Cis-RAC CH3-CH2CON (CH3) C2CH2OH CI-CH2CON (CH3) CH2CH2 OH 54 Cis-RAC CH3-CH2 CON (CH3) CH2CONH2C1CH2CON (CH3) CH2CONH2 Cis-RAC CH3-CH2CONnBu2 C1-CH2CONnBu2 Cis-RAC CH3-CH2CO- (1-piperidyl) C1-CH2CO- (1-piperidyl) 57 Cis-RAC CH-CH2CO-1-rorpholin CC- (1-morpholin CH3 2 {1-morpholin-4Cl-ORCDC- (1mulpholin) 3

  Cis-RAC CH3 4-methoxyphenylcarbonyloxy-4-methoxyphenyl chloride

  Methyl carbonyloxymethyl TABLE 2 (continued) Stereoisomerism Compound Compound Z R 'R2 R2Hal N Compound 1

  67 Cis-RAC CH3 3-methoxyphenylcarbonyloxy-3-methoxyphenyl chloride

  carbonyloxymethyl myl 68 Cis-RAC CH3-CH (CH3) OCOCH (CH2CH3> 2C1-CH (CH3) OCOCH (CH2CH3) 2 69 Cis-RAC CH3-CH2OCOC (CH3) 3 Ci-CH2OCOC (CH3) 3 Cis-RAC CH 2 CH 3 CH 2 CO 3 (CH 2 CH 3) 2 C1-CH 2 OCOCH (CH 2 CH 3 O) CH 2 CH 3 CHOCH (CH 3) OCOCH (CH 2 CH 3) 2 Cl-CH (CH 3) OCOCH (CH 2 CH 3) 2 Cis-RAC CH 2 CH 3 -CH 2 OCOCH (CEH 2 CH 3) 2 Cl-CH2OCOCH (CH2CH3) 2 73 Cis-RAC CH3-CH2COCH (CH2CH3) 2 Cl-CH2OCOCH (CH2CH3) 2 74 Cis-RAC CH3-CH2N (CH3) COPh C1-CH2N (CH3) COPh Cis-RAC CH3-CH (CH3> OCOOCH (CH3) 2 C! -CH (CH3) OCOOCH <CH3) 2

  Cis-RAC CH3 2-phenylbenzoyloxymethyl-2-phenylbenzoyl chloride

  oxymethyl TABLE 2 (continued) Compound Base Catalyst Solvent Temperature Solvent Duration [a] D 20 PF Lyser State 1st reaction stage reaction 2nd stage (1%, EtOH) Physical No (C) (oC) 1 NEt3 NaI DMF ambient 20 h THF resin

  2 DBU - ambient DMF 7 THF - - resin-

  3 DBU - DMF 55 6 THF - - resin 4 NEt3 - ambient THF 2 h THF - - DBU resin - ambient DMF 4 EtOAc +200 - resin (C = 1%, ETOH) - resin

  6 DBU - ambient DMF 3 'EtOAc - - resin.

  7 DBU - ambient DMF 3 EtOAc - - resin 8 NEt3 NaI DMF ambient 3 THF 132-135 colorless crystals 9 NEt3 NaI DMF ambient 4 THF - 65-67 solid white DBU - ambient DMF 4 EtOAc +7 44 58- 63 solid white

(C = 1%, ETOH) - resin.

  DBU - room DMF 24 h CH30OH - resine

  12 DBU - CH3CN 80 6 h THF - - Resin 13 NEt3 - Ambient THF 12 h TEF - Resin TABLE 2 (continued) Compound Base Catalyst Solvent Temperature Solvent Time [a] D 20 PF Lyser State 1st reaction stage reaction 2nd Step (1%, EtOH) Physical

N (OC) (C)

  14 NEt3 - Ambient THF 12 h THF - - resin

  NEt3 - ambient THF 12 h THF - - resin

  16 KOH - ambient DMF 24 h THF 102-109 whitish solid 17 DBU - ambient DMF 5 EtOAc - - resin 18 NEtiPr2 - ambient DMF 4 EtOAc +147 0 resin (C = 1% tETOH) 19 NEt3 NaI ambient DMF 3 * THF - 11Z0 - resin NEt3 NaI DMF room temperature 6 THF - - resin 21 NEt3 NaI DMF room temperature 24 h THF - 98-101 white solid 22 NEt3 NaI DMF room temperature 24 h THF 123-126 white solid 23 NEt3 NaI DMF room temperature 20 h THF 103-111 light yellow solid 29 NEt NaI DMF ambient 2 Colorless liquid THF TABLE 2 (continued) Compound Base CataSolvent Temperature Solvent Duration [], D 20 PF State lyser 1st reaction stage reaction 2nd stage (1%, EtOH) physical NO (OC) (oc) DBU - room DMF 3 EtOAc + 14.9 79-81 solid (C = 1% eETOH) white (ClX "To) white 31 DBU - room DMF 7 EtOAc - - resin 32 NEt3 NaI ambient DMF 3 THF 128- 132 colorless crystals 33 DBU - ambient DMF 4 EtOAc - 49-50 white solid 34 DBU - room DMF 20 h THF - - DBU resin - room DMF 20 h THF - 78- 84 solid 36 DBU - room DMF 18 h EtOAc +24, 55-56 solid (C = 0O5%, ETOH) white 37 DBU - room DMF 18 h EtOAc +22; 75-78 solid (C = 1105%, ETOH) white 38 NEt - ambient THF 12 h THF - - resin 39 NEt Ambient THF 12 h THF - NEt3 resin. - Ambient THF 12 hrs THF - - Resin 41 DBU - Ambient DMF 2 EtOAc + 14 i - Resin (C = 1%, ETOH) TABLE 2 (continued) Compound Base Catalyst Temperature Solvent Duration [a] D 20 PF lyser state 1st reaction stage reaction 2nd step (1%, EtOH) physical NO (Oc) (oc) lu

  42 DBU - ambient DMF 2 EtOAc +161 - resin-

(C = 17 ETOH) 43 DBU - room DMF 3 EtOAc +1073 "- resin

(C = 1%, ETOH)

  44 NEt NaI DMF Ambient 3 THF +11; 9 - Resin

(C = 1%, ETOH)

  DBU - ambient DMF 3 THF +8.8 - resin

(C = 1%, ETOH)

  46 NEt3 ambient NaI DMF 3 THF +9 - resin

  (C = 17% tETOH) 47 NEt3 NaI DMF Ambient 3j THF +77 - r-sine

(C = 1%, ETOH)

  48 NEt3 NaI DMF room temperature 3 THF +7 6a 45-53 solid (C = I, ETOH) white 49 NEt3 room temperature NaI DMF 24 h THF 123-124 room white solid NEt3 NaI DMF 24 h THF - 133-135 white solid TABLE 2 (continued) Compound Base Catalyst Solvent Temperature Solvent Duration [a] D 20 PF State lyser 1st reaction stage reaction 2nd stage (1%, EtOH) physical

N (OC) (OC)

  51 NEt3 NaI DMF room 24 h TBF-58-59 white solid 52 NEt NaI DMF room 24 h THF-76 solid 3 white 53 NEt NaI DMF room 24 h THF-waxy 54 NEt NaI DMF room 24 h THF-84-85 solid white NEt3 NaI DMF ambient 24 h THF - - Waxy 56 NEt3 Room temperature NaI DMF 24 - 49 white solid 57 NEt3 Room temperature NaI DMF 24 h THF - 41-45 solid white 66 DBU - room DMF 4 EtOAc - 62-64 solid white 67 DBU - Ambient DMF 4 EtOAc 49-51 solid white

  68 DBU - CH3CN 80 6 h THF - - reesin-

  TABLE 2 (continued) Compound Base Catalyst Solvent Temperature Solvent Duration [O] D 20 PF Lyser State 1st reaction stage reaction 2nd Stage (1%, EtOH) Physical No (OC) (oC) 69 DBU - Ambient DMF 4 THF - - resin

  DBU - ambient DMF 4 THF - - resin

  71 DBU - CH3CN 80 6 h THF - - resin 72 DBU - CH3CN 80 6 h THF - - liquid

  73DBU -_ Ambient DM 4. EtOAc - - resin.

  73 DBU - ambient DMF 4 EtOAc - - resin-

  74 DBU - ambient DMF 3 EtOAc - - resin'-

  NEt3 ambient NaI DMF 3 THF - - resin

  77 DBU - Ambient DMF 4 EtOAc - 60-64 solid white

TABLE 3

  Preparation of compounds of formula 1 according to scheme II (R2 = H) Stereoisomeria Compound Compound 4 R 'R2 R2Hal N Compound 1 24 Cis-1S, 2R) CH23-COC (CH3) 3 CICOC (CH3) 3 Cis (1S, 2R) CH3 -CO-adamantyl 1-adamantancarbonyl chloride

  Cis (1S, 2R) CH 3,4,5-trimethoxybenzoyl 3,4,5-trimethoxy chloride

  benzoyl Cis- (1S, 2R) CHR pyridint-3-carbonyl. nicotinoyl chloride Cis- (1S, 2R) CH3-COO (CH2) 3CH3 CICOO (CH2) 3CH3 58 C18- (1S, 2R) CH3 -COCH3 C1COOCH3 Cis- (18S, 2R) CH3 -COCH (CH2CH3) 2 C1COCH (CH2CH3) 2 Cis- (1S, 2R) CH3-CO (CH2) 10CH3Cl- CO (CH2) 10CH3Cl- (1S, 2R) CH3 -COPhCi-COPh 62Cis- (1S, 2R) CH3 2 2-Chlorobenzoylchlorobenzoyl Cis- (1S, 2R) CH 2 -Nitrobenzoyl 2-nitrobenzoyl chloride 64 C- (1S, 2R) CH 3 -COOCHCH 3 C-COOCH 2 CH- (1S, 2R) CH 3 -COOCH 2 Ph-C COOCH2Ph 76 Trans-RAC CH2CH3 -COPh C1-COPh Ns aqdowome @ aPTIOSo99-Z9 _.0u O a nana H HOsSN 2 aqdxoule N appTTiosoO-9OL - 0E 0 aHi / OH HOEN 19 XN xneIsTa.D oZS'-ETI o1 '+ DVOIS ## STR1 ## wherein X is the same as that of the above-mentioned formula, wherein X is at least one of the following groups: ## STR1 ## ## STR1 ## ouelq apTIoS99- S 6Cz- aHj- o 0 úH / Our HOeN 9a SDUE Tq GPTIos5 SI-E So6 (OZ q Eqquqquqquqqquqqquqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqqi Do) (Do) oN @nbTsLd UOTIeSTIITeST.XDUOT1DE9a apoTqDEaJ ap UOTq E9a ap 2; q * a * od 0 v Z [D] ap qUeAloSep eana axn; eadmeL IUEATOSeseesodmoD (aTFns) E flfTSvL 8Z Co s xqsTueO 0-9 N ah ', XflEIuSTD OSL-B- q Eo oa / OH HON 9L Gqdaowe' GPTIos 9- 08 O-q C o O HMH0 S9 auneC eptlos_ Gilt q O JHL / O0H HfON 9 aqdowme apTIos o0-Z9,0u [0 AHA / OH HOeN ú9 (Do) (Do) oUrbFs of UQUOttESTIITeSTaD UOT; tHe epuoTDEaI9a pUOTof9a Gp Ieq 'a 0 dO [D] epelecos ep ee9ne eanEcqtduaew ueAIoS its sS sodwoD

Claims (9)

  1. Compounds characterized in that they meet Formula 1 RO \ NH It ' I I 0 COOR   wherein R 'is a C1-C4 alkyl group; R2 is a C1-C12 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a C1-C4 alkoxy methyl group, a 2-tetrahydrofurylmethyl group, a 2-di (C1-C6) alkyl group; -C4) aminoethyl, -CH (R4) OCOR5, -CH (R4) COR6 or N-methylbenzamidylmethyl group;   R3 is hydrogen, a (C1-C6) alkoxy group -   carbonyl, benzyloxycarbonyl, (C 1 -C 2) alkylcarbonyl, adamantylcarbonyl, phenylcarbonyl optionally substituted with 1 to 3 substituents selected from Cl, NO 2 and OCH 3, or 3-pyridyl carbonyl; R4 is hydrogen or a C1-C6 alkyl group; R5 is C1-C12 alkyl, adamantyl, - (CH2) O2- (C4-C6) cycloalkyl, (C1-C6) alkyl-COOH, (alkyl) C1-C6) - CONR4, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-piperidine-1-benzoyl, phenyl optionally substituted with 1 to 3 substituents selected from R4, OCH3 , OH, OCOO (C1-C4) alkyl and Cl, a cis- or trans-2- [[[2- (hydroxyamino) -2-oxoethyl] (C1-C4 alkyl) aminolcarbonyl] lcyclohexyl group, an alkoxy group C 1 -C 6 cycloalkoxy optionally substituted with 1 or 2 substituents selected from R 4, or diphenyl-yl; R6 is - NR7R8, a 1-piperidinyl group or a 1-morpholinyl group; R7 and R8, which are the same or different, are each H, C1-C6 alkyl, phenyl, C1-C4 hydroxyalkyl, CH2CON (R4) 2, CH (COOH) CH2Ph or OH, and combinations; with the following conditions: - R2 and R3 are not simultaneously H; if R 'is a methyl group and R3 is hydrogen, then R2 is other than a methyl group or an acetyloxymethyl group; if R 'is an ethyl group and R2 is hydrogen, then R3 is other than an acetyl group; if R 1 is a methyl group, then R 2 and R 3 are not simultaneously CH 3, their non-toxic salts, their enantiomers or   isolated diastereoisomers and their relative mixtures.   2. Compounds according to claim 1, characterized in that R, is a methyl or ethyl group; R2 is hydrogen, C3-C12 alkyl, C3-C6 cycloalkyl, phenyl, (C1-C4) alkoxy methyl, 2-tetrahydrofurylmethyl,   2-di (C 1 -C 4 alkyl) aminoethyl group, an N-methyl group   benzamidylmethyl, CH (R4) OCOR5 or CH (R4) COR6; R3 is hydrogen, (C1-C6) alkoxycarbonyl, benzyloxycarbonyl, (C1-C12) alkylcarbonyl, adamantylcarbonyl or phenylcarbonyl   optionally substituted with 1 to 3 substituents selected from C1, NO2 and OCH3; R4 is hydrogen or a methyl group; R5 is a C4-C12 alkyl group, a - (CH2) 0-30 2-C4-C6 cycloalkyl group, a (C1-C6) alkyl -COOH group, a (C1-C6) alkyl group -CONR42 , a 2-, 3- or 4- group   piperidinyl, a 2-, 3- or 4-piperidine-1-benzoyl group, a diphenylyl group, a phenyl group optionally substituted with 1 to 3 substituents selected from R4, OCH3, OH, OCOO (C1-C4) alkyl and Cl, a cis- or trans-2 - [[[2-   (hydroxyamino) -2-oxoethyl] - (C 1 -C 4) alkylamino] carbonyl] -   cyclohexyl, a C1-C6 alkoxy group or a C4-C6 cycloalkoxy group optionally substituted with 1 or 2   substituents selected from R4; R6 is as defined above   above; with the proviso that R2 and R3 are not simultaneously hydrogen. 3. Compounds according to claim 1, characterized in that R3 is hydrogen and R2 is a lower alkyl group.   C3-C12, preferably C6-Cl2 alkyl, a 2-   tetrahydrofurylmethyl, a methoxymethyl group, a 2-ethylaminoethyl group or a group of the formula CH (R4) OCOR5 wherein R4 is hydrogen or a methyl group and R5 is a C4-C12 alkyl, (CH2) O1-cyclohexyl, (alkyl) C3-C4) -COOH, (C3-C4 alkyl) -CONEt2, piperidinyl,   piperidine-1-benzoyl, adamantyl, N-methylbenzamidyl-   methyl, phenyl optionally substituted with 1 to 3 substituents selected from R4, OCH3, OH, OCOO (alkyl C1-C4) and Cl, or diphenylyl.   4. Compounds according to claim 1, characterized in that R3 is hydrogen and R2 is a group of formula CH (R4-) COR6 where R4 is hydrogen and R6 is -NR7R8 o R7 and R8, which are the same or different, are each hydrogen,   C1-C6 alkyl, C1-C4 hydroxyalkyl, CH2CONH2, CH (COOH) CH2Ph or OH, or R7 and R8, taken together with the nitrogen atom to which they are attached, form a 1-25 piperidinyl ring or 1-morpholinyl.   5. Compounds according to claim 1, characterized in that R3 is hydrogen and R2 is a group of formula   CH (R 4) OCOR 5 wherein R 4 is hydrogen or a methyl group and R 5 is a C 1 -C 6 alkoxy group or a C 4 -C 6 cycloalkoxy group optionally substituted with 1 or 2 substituents selected from R 4.   6. Compounds according to claim 1, characterized in that R2 is hydrogen and R3 is a C1-C4 alkoxycarbonyl group, a benzyloxycarbonyl group, a C1-C12alkylcarbonyl group, a phenylcarbonyl group optionally substituted with 1 to 3 substituents selected from Cl, NO2 and OCH3, an adamantylcarbonyl group or a   3-pyridylcarbonyl group. 7. Process for the preparation of compounds of claims 1 to 6, characterized in that it comprises the   reaction of a compound of Formula 2 OCH2Ph o1 wherein R 'is as defined above with a   halogenated compound of formula R2Hal, where Hal is chlorine, bromine or iodine and R2 is as defined above, followed by removal of the benzyl group. 8. Process for the preparation of compounds of claims 1 to 6, characterized in that it comprises the   reaction of a compound of Formula NH RI \ oI co3- O COOH   wherein R, is as defined above, with a   compound of formula R3Hal, where Hal is chlorine, bromine or iodine and R3 is as defined above.   9. Pharmaceutical compositions, characterized in that they contain a compound of claims 1 to 6 as an active ingredient.