FI84481B - Process for preparing novel antihypertensive 7-amino- 1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido/2,1-a//2/- benzazepine-4-carboxylic acid derivatives - Google Patents

Abstract

The invention relates to 6-oxopyrido(2,1-α) and (1,4)thiazino(3,4-a)(2)benzazepine-4-carboxylic acid derivatives and their preparation and also to intermediates which can be used in the preparation. The said derivatives have a pharmacological effect by inhibiting angiotensin converting enzyme and they can be used for treating hypertension. The novel compounds have the formula <IMAGE> in which R and R1 are independently hydrogen; alkyl; substituted alkyl; aryl; substituted aryl; heteroaryl; or substituted heteroaryloxy; R2 is hydrogen, straight-chain or branched alkyl, alkenyl or alkinyl; cycloalkyl, arylalkyl; or substituted alkyl; R3 is H, alkyl, phenyl or benzyl; R4 is a natural amino acid residue, and R3 and R4 have been linked, by way of the carbon atoms to which they are bonded, in order to form a 6-8-membered condensed ring which optionally contains a sulfur or oxygen atom, and R5 and R6 are independently hydrogen, hydroxyl; halogen; alkyl; or alkyloxy.

Description

1 84481

The present invention relates to a process for the preparation of novel antihypertensive 7-amino-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido [2,1-a] [2] -benzazepine-4-carboxylic acid derivatives. preparation of tricyclic lactam derivatives. The compounds are pharmacologically active in inhibiting angiotensin converting enzyme and can be used in the treatment of hypertension. The related prior art has been described e.g. U.S. Patent No. 4,584,294, which discloses structurally related compounds having the same type of therapeutic effect.

The invention relates to a process for the preparation of therapeutically useful 7-amino-1,2,3,4,6,7,15,12b-octahydro-6-oxopyrido [2,1-a] [2] benzazepine-4 of formula (II). - for the preparation of carboxylic acid derivatives and their pharmaceutically acceptable salts, 20 ^ R'100C (r f2

I UH

n-2H 11 · 25 2 H O COOR 'wherein R' is hydrogen, C 1-6 alkyl or diphenylmethyl; R 1j is hydrogen or C 1-6 alkyl; and R '2 is hydrogen or phenyl-C 1-6 alkyl.

Alkyl groups include, for example, methyl, ethyl, vinyl, propargyl, butenyl, isobutyl and the like.

Preferred compounds are those compounds wherein R '35 is hydrogen, R' 1 is hydrogen or ethyl and R '2 is phenethyl.

2 84481

The compounds of the invention (II) are prepared according to the invention by reacting a fused lactam of the formula (XXII) (f ch2 J (XXII) 10 H2N U i u COOR 'with a reagent of the formula (A).

I 2 1 R'2CH (A) 5so2cf3 in which R 'and R'x are other than hydrogen, in the presence of a base and, if desired, one or both of the ester groups R' and R'x are removed.

The compounds of formula (II) are prepared by a series of reaction steps known per se in the art. It is generally preferred to start the series using the appropriate 25 N-protected arylalanine which, upon conversion to the acid chloride, is combined with the appropriate amine according to well known Schott-Baumann principles. Prior to coupling methods to the nitrogen atom attached to the 3-position in the benzazepin-2-one moiety, the appropriate intermediates are subjected to a Friedel-Kraft cyclization reaction. The N-protecting group (e.g., a phthalimido moiety) is removed from the cyclization residue and the nitrogen atom is subjected to standard coupling procedures to give the desired compounds of formula (II) containing R 1 and R 12.

The N-protected arylalanine acid chloride derivatives (III) are coupled by treatment with aminovinyl chloride 3,84881 (IXa) or -OH-protected vinylamino acid (IXb) according to the Schott-Baumann reaction described above to give intermediates (Xa and Xb, respectively). These intermediates are treated with ozone in methylene chloride containing alcohol at -78 ° C, quenched with dimethyl sulfide and pyridine, and the isolated products are treated with trifluoroacetic acid / methylene chloride at reflux to give acyl amines (Xb) and (Xla), and (Xla) CF 3 SO 3 H according to the Friedel-Kraft ring-10 ring method to form compounds Xlla and Xllb. To effect Friedel-Kraft cyclization, it is preferred to use a Lewis acid, which is preferably a perfluoroalkylsulfonic acid such as trifluoromethanesulfonic acid, pentafluoroethanesulfonic acid and heptafluoropropanesulfonic acid. These reactions are shown in Reaction Scheme B.

4,844S1

Reaction Scheme B

R6-xS \ d V7 Γ ^ Ί [fVR5 H »N T - *

5 cl cl PgN ^ * · T

W "IXa Xa G

0 III

I Rs Rs 10 'Coupling> SK ^ \ C ^ s, (CH2) n___ ^ 111 + - ^ CO, R NH (CH2) n H2N CO2R PgN / »f

IXb c ° 2R

15 Xb ”6> <i> R5 R6> ^ N ^ r5 ** i) o3.roh 'feJT +

tal £ Me2S_ ^ ί, Ν ^ Y

20 Xb 3> hQ PgN * Ö PgN / T Y (CH2) n., Co2r co2r ^ Xlb I Lewis acid. Lewis acid 25, R6 V R5 Re y — _ R5 30 Vx ^ .N (CH2) „., Vx ^ n '(CH2)„.,

P9n '»Y / H V

Ok PgN O

CO2R co2r XMb 35 s 84481 where R = R ', R5, R6 are hydrogen, Pg is an N-protecting group (preferably forms a phthalimido) and n is 3.

In reactions in which the fused lactam is prepared by Friedel-Kraft cyclization methods, it is, of course, preferred to use perfluoroalkylsulfonic acid.

Once the fused lactam (e.g., XIIa, XIIb) has been prepared, the N-protecting group is removed so that the appropriate side chain can be coupled to the free amine. This deprotection 10 can be performed by standard methods. In cases where the protecting group is phthaloyl, it is most preferable to remove the phthalimido moiety by reaction with hydrazine hydrate by methods well known in the art. Although all diastereomeric forms of fused lactams are included in the invention, the preferred deprotected fused lactams have the following structure:

'n I

h2n q 1 υ co2r '

XXII

25 where R 'is other than H.

Although the usual methods commonly used in such couplings can be used, preferred methods for such couplings are shown in Reaction Scheme E.

6 84481

Reaction Scheme E

CO 2 R '// S

s (R) I R ', 04 \ Wy Λ. 2 i -► M CIIIH \ 'hi "MII + OSO2CF3 / \

and 11 T

XXIII 0 CO2R '10

XXVI

wherein R 'and R'x are as defined above, except that they cannot be hydrogen, and R'2 is as defined above. It should also be noted that although the preferred diastereomeric form of the fused lactams is represented by Formula XXVI, all diastereomeric forms may be prepared by analogous methods.

In Method A, Scheme E shows a substitution reaction (R) with triflate (XXIII) in which the fused lactams are combined with triflate in the presence of a base, e.g. triethylamine, but more preferably in the presence of a "proton collector", i.e. 1,8-bis- (di- in the presence of methylamino naphthalene to give compounds XXVI.

Since a preferred embodiment of the present invention relates to those compounds of formula II wherein R 'is H and R'x is other than H (preferably ethyl), certain aspects need to be considered in connection with the above coupling methods for Reaction Scheme E, in particular because they concerning the selective hydrolysis of R ester groups. For example, in general, for the selective hydrolysis of compounds XXVI, it is preferable to prepare esters wherein R is diphenylmethyl, triphenylmethyl or benzyl, as these groups can be selectively hydrolyzed with weak acids, for example by reaction with ethereal hydrochloric acid or trifluoroacetic acid, or otherwise hydrogenated. lysis. Each R group (other than H) can be selectively hydrolyzed to the corresponding acid by treatment with perfluoroalkylsulfonic acid. Suitable perfluoroalkyl-5-sulfonic acids include trifluoromethanesulfonic acid, pentafluoroethanesulfonic acid and heptafluoropropanesulfonic acid.

The compounds of formula (II) form salts with various inorganic and organic acids and bases and are also within the scope of the invention. These salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-Glu-15amine, salts with amino acids such as arginine, lysine or lysine. Salts can also be prepared with organic and inorganic acids, e.g. HCl, HBr, H 2 CO 3, H 3 PO 4, methanesulfonic, toluenesulfonic, maleic, ant camphor sulfonic acids. Physiologically acceptable salts are preferred, although other salts may also be used, for example, in the isolation or purification of the product.

The salts may be prepared by conventional methods such as reaction of the free acid form or base form of the product with one or more equivalents of a suitable base or acid in a solvent or medium insoluble or in a solvent such as water, which is then removed in vacuo or freeze-dried or cationized. 30 days in ion exchange resin.

The compounds of this invention inhibit an angiotensin converting enzyme and thus prevent the conversion of decapeptide angiotensin I to angiotensin II. Angio-tensin II is a potent antihypertensive agent. The decrease in blood pressure of Si-35 may be due to inhibition of its biosynthesis, especially in animals and humans with high blood pressure due to angiotensin II. In addition, the altering enzyme can also lower blood pressure with bradykinin enhancement. Although the relative importance of these and other possible mechanisms remains to be determined, angiotensin-converting enzyme inhibitors are potent antihypertensive agents in a variety of animal studies and are clinically useful, for example, in many human patients with renal-onset renal and vascular malignancy. See, e.g., D.W. Cushman, et al., Biochemistry 16, 5484 (1977).

Evaluation of transforming enzyme inhibitors is presented outside of the living organism by enzyme inhibition assays. A useful method is, for example, Y. 15 Piquilloud, A. Reinharz and M. Roth, Biochem. Biophys.

Acta, 206 N36 (1970), which measures the hydrolysis of carbobenzyloxy-phenylalanylhistidinyl leucine. Evaluations in a living organism are performed, for example, in rats with normal blood pressure treated with angiotensin I by the method of J.R. Weeks and J.A. Jones, Proc. Soc. Exp. Biol. Med., 104, 646 (1960) or in a rat model with a high renin content, as reported by S. Koletsky et al., Proc. Soc. Exp. Biol. Med. 125, 96 (1967).

To demonstrate the inventive nature of the compounds of formula (II), the therapeutic activity of the compound of Example 7 (Compound B) was compared to the closest structural compound known from U.S. Patent 4,584,294, represented by Formula (A) below: 30 35 9 84481

3 — cooH CO OH

¢¢. CQ.

5 NH NH

L 1

CH-COOH CH-COOH

9H2 ch2 A Λ u u (AJ (B) 15

Inhibition of rabbit lung ACE by test compounds was studied in vitro using the radiometric assay described in E. Giroux, D.W. Beight, R.C. Dage & G.A. Flynn, "Interaction of angioten-20 sin I-Converting enzyme with two potent tricyclic inhibitors", Journal of Enzyme Inhibition 2 (1982) 267-277. The concentration of inhibitor required to reduce the activity of the enzyme to half its normal value was determined at three different enzyme concentrations. The results obtained 25 are shown in the following table: 10 84481

Enzyme content IC50A IC50B

0.125 μΐ 1.125 nM 0.174 nM

Δ 0.125 μΐ 0.632 nM 0.170 nM

0.025 μΐ 0.241 nM 0.242 nM

0.025 μΐ 1.510 nM 0.274 nM

0.025 μΐ 2.272 nM 0.567 nM

0.05 μΐ 1.364 nM

0.05 μΐ 1.4 nM

0.05 μΐ 1.734 nM 0.658 nM

0.05 μΐ 0.416 nM 0.556 nM

0.05 μΐ 0.759 nM 0.398 nM

15

In six of the eight simultaneous experiments, compound (B), i.e. the compound of the invention, was more potent, i.e. a lower concentration was required to achieve 50% inhibition. In one experiment, the potency 20 was the same for both test compounds, and in one experiment, the compound (B) of the invention was less effective than the reference compound (A).

When the results are presented graphically, the coordinate intersection point Kt for compound (A) is 0.94 nM, while the corresponding value for compound (B) is 0.004 nM. The potency ratio in favor of the compound (B) of the invention is thus more than 200 times that of the reference compound (A) as determined by the β-values.

The compounds of the invention are thus useful as antihypertensive agents in the treatment of high blood pressure mammals, including humans, and can be used to lower blood pressure by controlling them into suitable dosage forms. The compounds of the invention may be administered to patients in need of such treatment in a dose range of 0.5 to 100 mg per patient, usually administered several times a day, i.e. a total daily dose of 0.5 to 400 mg per day. The dose will vary according to the severity of the disease, the weight of the patient and other factors considered by a person skilled in the art.

Preferred subclasses of compounds are those compounds of the following formula

10 S

R'100C \ FR CH2 - "tsN N * Il jP> R'2 h" 10 COOR '15 wherein R'2 is phenethyl, R' is C1-4 alkyl or H, and R'j is ethyl.

The following examples illustrate methods and conditions under which the compounds of the invention may be prepared. The preferred diastereomers of these examples can be isolated by conventional methods.

Example 1 [2 (S)] N- (2-chloro-2-cyclohexen-1-yl) -1,3-di-hydro-1,3-dioxo-2H-isoindole-2- (S) - ( phenylmethyl-2-acetamide (Xa))

Step A. 2- (2-Chloro-2-chloro-2-cyclohexen-1-yl) -1H-isoindole-1,3 (2H) -dione A solution of 11.0 g (72.8 mmol) ) 1,6-dichloro-30-cyclohexane, 20.0 g (108 mmol) of potassium phthalimide and 1.0 g (6.0 mmol) of potassium iodide in 50 ml of dry dimethylformamide (DMF) were stirred for 24 hours at 110 ° In C in the nitrogen atmosphere. The reaction mixture was allowed to cool and then any diethyl ether was poured. The dark mixture was filtered and then the ether and DMF were removed under reduced pressure. The dark crystalline residue was dissolved in ethyl acetate, then chromatographed on 84 g of silica eluting with 10-20% ethyl acetate-hexane. The appropriate fractions were concentrated and recrystallized from ethyl acetate-hexane to give 14.0 g (73.5%) of the desired phthalimide, m.p. 99-103 ° C.

Step B. A solution of 6.0 g (120 mmol) of hydrazine hydrate and 26.1 g (100 mmol) of N-phthalimido-6-amino-1-chlorocyclohexene in 150 mL of MeOH was heated to reflux under N 2. for three hours, cooled to 25 ° C and stirred for three hours. The mixture was filtered, concentrated, poured into 300 mL of 1N HCl and washed with 200 mL of CH 2 Cl 2. The aqueous layer was basified and extracted three times with 500 mL portions of CH 2 Cl 2. The organic phases were dried over MgSO 4, filtered and concentrated to give 9.25 g (70 mmol) of crude amine. The neutral extract was concentrated to give 6.0 g of unreacted starting phthalimide. To a stirred solution of 21 g (71 mmol) of phthalimido-L-phenylalanine and 18.5 g (75 mmol) of EEDQ in 200 mL of CH 2 Cl 2 at 25 ° C in 20 N was added 9.25 g (70 mmol) of 6-amino-1-chlorocyclohexene in 20 ml of CH 2 Cl 2 over 30 minutes. After stirring for 18 h, the reaction mixture was washed with two 200 mL portions of 10% HCl, 200 mL of NaHCO 3 and brine. The organic phases were dried over MgSO 4, filtered and concentrated to give a solid. Recrystallization from CH 2 Cl 2 / hexane gave 26.1 g of a mixture of the desired 2- (S) -diastereomeric amides (Xa) which was not isolated at this stage. (64% overall yield):

IR (KBr) 3400, 1775, 1715, 1650, 1530, 1380, cm -1; NMR

61.60 (m, 2H), 1.82 (m, 2H), 2.05 (m, 2H), 3.49 (s, 1H), 3.59 (s, 1H), 4.60 (m , 1H), 5.05 (dd, 1 / 2H, Ja = 10Hz, Jb = 2Hz), 5.17 (dd, 1 / 2H, Ja = 10Hz, Jb = 2Hz), 5.95 (t, 1H, J = 7 Hz), 6.45 (m, 1H), 7.10 (s, 5H), 7.70 (m, 4H).

35 i3 84 481

Analysis for C23H21ClN2O3:

Calculated: C 67.56 H 5.18 N 6.85 Found: C 67.40 H 5.30 N 6.80

Example 2 5 [S (R *, R *)] - 1- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl ] -1,2,3,4-tetrahydro-2-pyridinecarboxylic acid, methyl ester (Xla)

A solution of 12.2 g (30 mmol) of vinyl chlorides from Example 10 (Xa) in 300 ml of CH 2 Cl 2 with 20 ml of abx. MeOH, cooled to -70 ° C and stirred while passing a stream of ozone in oxygen (generated by a Wels-Bach Ozonator) through sintered glass. When the solution turned blue, excess ozone was removed by lowering the solution to N2. The reaction mixture was treated with 20 mL of Me 2 S and 4 mL of pyridine and then allowed to gradually warm to 25 ° C and stirred for 20 hours. The solution was poured into 200 mL of 10% HCl solution and the organics were separated, washed well with H 2 O, dried over MgSO 4 and concentrated to give 13.0 g of an amber oil. The crude ozonolysis product was dissolved in 200 mL of CH 2 Cl 2 with 0.5 mL of trifluoroacetic acid (TFA) and the reflux was cooled in N 2 for three hours. The cooled solution was washed with saturated NaHCO 3 solution, dried over 25 MgSO 4 and concentrated to give 12.2 g of an amber oil. Preparative HPLC separation using 50% EtOAc / hexane (Waters Prep-500 single repeat) afforded 4.3 g (10.1 mmol) of each diastereomeric acyl enamine Xla and Xlb (n = 2), (68% size -30 female yield). Isomer Xla was recrystallized from CH 2 Cl 2 / hexane to give a fine white crystalline powder: m.p. 146-147 ° C; [Α] D = - 320.1 ° (c = 1.1, CHCl 3); IR (KBr) 1770, 1740, 1720, 1670, 1650, 1390, 1220, 722 cm-1; NMR 61.85 (m, 2H), 2.30 δ (m, 2H), 3'50 (d, 2H, J = 7 Hz), 3.72 (s, 3H), 4.71 (m, 1H) ), 14 84481 5.20 (m, 1H), 5.27 (t, 1H, J = 7Hz), 6.45 (d, 1H, J = 9Hz), 7.12 (s, 5H), 7.71 (m. 4H).

Analysis for C23H22N2O5:

Calculated: C 68.89 H 5.30 N 6.69 5 Found: C 68.61 H 5.26 N 6.56

Example 3 [4S- (4a, 7a, 12b6)] - 7- (1,3-dihydro-1,3-dioxo-2H-isoindo-2-yl) -1,2,3,4,6, 7,8,12b-Octahydro-6-oxopyrido [2,1-a] [2] benzazepine-4-carboxylic acid, 10-diphenylmethyl ester * (Xlla)

To a stirred solution of 4.20 g (10.0 mmol) of the desired acyleneamide Xla from Example 2 in 20 mL of CH 2 Cl 2 under N 2 was added 6 mL of CF 3 SO 3 H. After stirring at 20 ° C for 18 h, the solution was poured onto ice and extracted with 200 mL of EtOAc. The organics were washed well with water, dried over MgSO 4 and concentrated. The residue was dissolved in CH 2 Cl 2 and treated with 2.2 g of diazodiphenylmethane and allowed to stand for 12 hours. The solution was concentrated and the residue was chromatographed on 400 mL of silica using 33% EtOAc / hexane to give 4.5 g (7.7 mmol, 77% yield) of benzhydryl ester XII (R 2 CHPh 2) as a foam. Recrystallization from CH 2 Cl 2 / hexane was slow, but 4.3 g (75% yield) of clear transparent plates were obtained: m.p. 156-157 ° C; [α] D = -87.6 ° C (c = 0.6, CHCl 3), IR 1780, 1717, 1643, 1450, 1379 cm -1; NMR 61.8-2.1 (m, 4H), 2.38 (m, 2H); 3.23 (dd, 1H, Ja »18 Hz, Jb = 16 Hz), 4.38 (dd, 1H, Ja = 19 Hz, Jb = 12 Hz), 5.30 (dd, 1H, Ja = 6 Hz) ,

Jb-2 Hz), 5.42 (dd, 1H, Ja = 6 Hz, Jb = 4 Hz, 6.05 (dd, 1H,

Ja = 12 Hz, Jb = 6 Hz), 6.30 (s, 1H), 6.61 (d, 1H, J = 7 Hz), 6.9-7.4 (m, 13 H), 7 .75 (m, 2H); 7.92 (m, 2H).

Analysis for C36H30N2O5:

Calculated: C 75.77 H 5.30 N 4.91 Found: C 75.79 H 5.46 N 4.77 * (Compound of Formula XII wherein R is diphenylmethyl-35 and R 5 and R 6 are hydrogen and n is 3).

15 84481

Example 4 [4S- (4a, 7a, 12b8)] -7- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1,2,3,4,6, 7,8,12b-Octahydro-6-oxapyyrido [1a] [2] benzazepine-4-carboxylic acid, methyl 5-ester

Alternatively, the cyclization product can be treated with diazomethane to give the methyl ester XII from Example 3 (R = CH 3): m.p. 138-149 ° C; [α] D 20 -122.4 ° (c = 0.97, EtOH); IR 1778, 1720, 1655, 1620, δ 1375 cm -1, NMR δ 1.7-2.2 (m, 4H), 2.43 (m, 2H), 3.10 (s, 3H), δ, 44 (dd, 1H, Ja = 17 Hz, Jb = 6 Hz), 4.42 (dd, 1H, Ja = 17 Hz, Jb = 12 Hz), 5.23 (dd, 1H, Ja = 6 Hz, Jb = 2 Hz), 5.47 (dd, 1H, Ja »6 Hz, Jb = 4 Hz), 6.08 (dd, 1H, Ja = 12 Hz, Jb = 6 Hz), 7.23 (m, 4H ), 7.77 (m, 2 H), 7.89 (m, 2 H).

Analysis for C24H22N2O5:

Calculated: C 68.89 H 5.30 N 6.69 Found: C 68.98 H 5.83 N 6.63

Example 5 (4a, 7a, 12b8) -7 - [[1- (Ethoxycarbonyl) -3-phenyl-propyl] amino] -1,2,3,4,6,7,8,12b-octahydro-6-ol Oxopyrido [2,1-a] [2] benzazepine-4-carboxylic acid, phenylmethyl ester (Ha)

To a solution of 1.17 g (2.0 mmol) of phthalimide XII from Example 3 (R = CHPh 2) in 15 mL of dry MeOH was added 2.3 mL of a 1N solution of hydrazine hydrate in MeOH and the solution was stirred at 25 °. In C for three days. The solvent was removed in vacuo to give a residue which was dissolved in CHCl 3, filtered and concentrated to give the crude amine as a pale yellow oil. This crude amine (ca. 2.0 mmol) was dissolved in 6 mL of CH 2 Cl 2 under N 2 at 25 ° C and treated with 545 mg (2.5 mmol) of 1,8-bis- (dimethylamino) naphthalene and then 850 mg (11a) (2.5 mmol) of (R) -ethyl 4-phenyl-2-trifluoromethanesulfonyloxybutanoate (XXIII). The solution was stirred at 25 ° C-35 for 18 hours during which time a precipitate formed. The reaction mixture, i.e. 84481, was applied directly to 100 mL of silica gel and chromatographed using 25% EtOAc / hexane to give 1.11 g (1.76 mmol) of 88% yield of pure S, S, S, R-diester ( Ha) (R 3, R 4 = -CH 2 CH 2 CH 2 -, R = CHPh 2) as an oil: δ IR (KBr) 1734, 1657, 1495, 1452, 1185, 1155 cm -1; NMR δ 1.28 (t, 2H, J * 7 Hz), 1.7-2.2 (m, 6H), 2.43 (m, 2H), 2.68 (dd, 1H, Ja = 17 Hz) , Jb = 13 Hz), 2.80 (m, 2H), 3.25 (dd, 1H, Ja = 17 Hz, Jb = 6 Hz), 3.46 (t, 1H, J = 7 Hz), 4 , 17 (q, 1H, J = 7 Hz), 4.38 (dd, 1H, Ja = 13 Hz, Jb = 6 Hz), 5.35 (dd, 1H, Ja = 6 10 Hz, J = 4 Hz ), 5.40 (dd, 1H, Ja = 6 Hz, Jb = 2 Hz), 6.25 (s, 1H).

Example 6 [4a, 7a (R *), 12bö] -7 - [[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1,2,3,4,6,7,12b-octahydro-6 -oc-15-pyryrido [2,1-a] [2] benzazepine-4-carboxylic acid (II)

To a stirred solution of 900 mg (1.42 mmol) of (S, S, S, R) -benzhydryl ester from Example 5 (R3, R4 = -CH2CH2CH2-, R = CHPh2) and 2.5 ml of anisole at 25 ° C: under a nitrogen atmosphere, 7 ml of trifluoroacetic acid were added.

After stirring for two hours, the volatiles were removed under high vacuum to give an oily residue which was dissolved in 4 mL of dry ether, stirred vigorously and diluted with hexane. The supernatant was decanted from a gummy solid which was triturated with hexane and dried in vacuo to give 750 mg (1.3 mmol) of a light brown solid (S, S, S, R) II TFA salt (R 3, R 4 = - CH 2 CH 2 CH 2 -, R = H) (91% yield): [α] D = 25.5 ° C (c = 0.57, CH 3 OH); IR (KBr) 2300-3400, 1735, 30 1660, 1195, 1140 cm-1; NMR δ (CD 3 CN, TFA) 1.31 (t, 3H, J = 7

Hz), 1.78 (m, 2H), 2.3-2.5 (m, 4H), 2.84 (m, 2H), 3.26 (dd, 1H, Ja = 17 Hz, Jb = 13 Hz, 3.68 (dd, 1H, Ja = 17 Hz, Jb = 6 Hz), 4.07 (t, 1H, J = 6 Hz), 4.29 (m, 2H), 5.10 (dd, 1H, Ja »6 Hz), Jb = 2 Hz) 5.20 (dd, 1H, Ja = 13 Hz, Jb = 6 Hz), 5.35 (dd, 1H, 35 Ja = 5 Hz, Jb = 1 Hz) ), 7.1-7.4 (m. 9H).

i7 84481

Analysis ^ 29 ^ 33 ^ 3 ^ 2 ^ 7 * ϋ® ·

Calculated: C 60.20 H 5.75 N 4.84 Found: C 60.12 H 5.72 N 4.45

Example 7 5 [4a, 7a (R *), 12b8] -7 - [[1-carboxy-3-phenylpropyl] amino] -1,2,3,4,6,7,12b-octahydro-6-oxopyrido - [2,1-a] [2] benzazepine-4-carboxylic acid (II) To a solution of 116 mg (0.20 mmol) of ester (II R = H, R3, R4 -CH2CH2CH2- from Example 6) in 5 ml: in 95-10% EtOH under N 2 at 25 ° C, 0.50 mL of 1N LiOH stock solution was added. After stirring for 18 hours, 0.50 mL of 1N HCl was added dropwise with vigorous stirring. The zwitterion was isolated by filtration and dried in vacuo to give 80 mg (0.17 mmol) of 85% yield of a white solid which was homogenized by analytical HPLC (Whatman Partisil 10 0DS-3 column, 0.1M ammonium formate buffer). In 50% MeOH / H 2 O). Repeating the analytical treatment on a portion of the sample gave 8 mg of fine colorless crystals from elution buffer: m.p.

209-260 ° C (dec.); [α] D 25 = + 24 ° (c = 0.05, MeOH); IR (KBr) 1745, 1653, 1630, 1495, 1420, 1305, 1220, 752, 695 cm-1; NMR (CD 3 CN, TFA) δ 1.80 (m, 4H), 2.3-2.4 (m, 2H), 2.9 (m, 2H), 3.29 (dd, 1H, Ja-17 Hz) , Jb = 13 Hz), 370 (dd, 1H, Ja = 17 Hz, Jb = 6 Hz), 4.13 (dd, 25 1H, Ja = 10 Hz, Jb = 5 Hz), 5.13 (dd, 1H, Ja = 6 H :, Jb = 2 Hz), 5.24 (dd, 1H, Ja = 13 Hz), Jb = 6 Hz), 5.36 (dd, 1H, Ja = 6 Hz, Jb-1 Hz), 7.2-7.4 (m. 9H).

Analysis for C25H21N2O5:

Calculated: C 68.79 H 6.46 N 6.42 30 Found: C 68.49 H 6.53 N 6.50

Example 8 2-Amino-5-heptenoic acid, methyl ester To a solution of 15.4 mL (110 mmol) of diisopropylamine in 250 mL of dry THF at -78 ° C was added 35 39 mL (105 mmol) of 2 .7 M n-butyllithium in hexane. Cell 84481 was stirred for 30 minutes and then 20 mL of hexamethylphosphoric triamine and a solution of 17.7 g (100 mmol) of benzaldehyde Schiff's base and glycine methyl ester in 25 mL of THF were added over 30 minutes. After 15 minutes, 13.5 g (100 mmol) of 5-bromo-1-pentene were added and the solution was allowed to slowly warm to 25 ° C. After 3 hours, the reaction mixture was poured into water and extracted with ether. The extracts were washed repeatedly with brine, then dried over MgSO 4 and concentrated to give 25 g of an amber oil. This material was dissolved in 40 mL of ether and stirred with 300 mL of 0.5N HCl for two hours. The aqueous layer was separated and the pH was adjusted to 9 with 1 N NaOH. Extracted with chloroform, dried over MgSO 4 and concentrated to give 4.5 g of the desired product as a liquid.

By adding 5-bromo-1-pentene to an equal amount of 6-bromo-1-hexene or 7-bromo-1-heptene and following the procedures of this example, 2-amino-6-octanoic acid and 2-amino-7-nonenoin-20 were prepared, respectively. acid methyl esters. (These three compounds correspond to compounds of formula IXb where n is 3, 4 or 5, respectively.)

Example 9 2 - [[2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -25'-oxo-3-phenylpropyl] amino] -6-heptenoic acid, methyl ester

To a solution of 6.0 g (20 mmol) of phthalimido-L-phenylalanine and 6.0 g (24 mmol) of EEDQ in 30 mL of CH 2 Cl 2 was added (21 mmol) of the product of Example 8 in 10 mL of 30 mL of CH 2 Cl 2. gas evolution and stirring were continued for 18 h, the solution was diluted with CH 2 Cl 2, washed with 10% HCl solution, saturated NaHCO 3 solution and dried over MgSO 4, and concentrated to give 8.3 g of a yellow oil which was chromatographed on 25 ° C. % EtOAc / hexane to give 6.0 g of di-stereomeric amides Xb (n * 3) as a foam.

i9 84481

Similarly, by adding 2-amino-5-heptenoic acid methyl ester and equal amounts of 2-amino-6-octenoic acid methyl ester or 2-amino-7-nonenoic acid methyl ester and following the procedures of this example, the corresponding compounds of formula Xb were obtained, where n is 4 and 5, respectively.

Example 10 1,2,3,4-Tetrahydro-1- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] py-10 ridine-2-carboxylic acid, methyl ester

The olefin of Example 9 (10 mmol) was dissolved in 100 mL of CH 2 Cl 2 with 10 mL of absolute MeOH and cooled to -78 ° C. A stream of ozone was added to the solution while stirring until a blue color developed.

N 2 was added to the solution and then 10 ml of dimethyl sulfide and 0.5 ml of pyridine were added and the solution was allowed to slowly warm to 25 ° C and stirred for 18 hours. The solution was washed with three portions of 10% HCl, dried over MgSO 4 and concentrated to give an oil. This crude product was dissolved in 150 ml of trichloroethane and treated with 0.5 ml of trifluoroacetic acid under reflux for 18 hours. Concentration and chromatography afforded chromatographically separable diastereomeric acyl amines Xla and Xlb (n <3).

Example 11 7- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido [2 , 1-a] [2] Benzazepine-4-carboxylic acid, diphenylmethyl ester The desired acyl enamine (1.6 mmol) (Xla) from Example 10 was dissolved in 5 mL of CH 2 Cl 2 and treated with 2.0 mL. trifluoromethanesulfonic acid at 25 ° C under N 2 for 18 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed well with water, concentrated and treated with excess diazodiphenylmethane in CH 2 Cl 2.

20 8 4 4 81

Chromatography gave the cyclized ester XIIa (n * 3, R CHPh2) as a foam.

According to the chemical methods set forth in Examples 8-11, using 6-bromo-1-hexene-5 and 7-bromo-1-heptene, homologous tricyclic intermediates Xlla (n = 4) and Xlla (n = 5), respectively, are obtained.

As shown in Example 5, these homologous intermediates XII (n = 4.5) are treated with hydrazine to deprotect and coupled to R-triflate of type XXIII to give diesters II (R 3 'R 4 = -CH 2 - (CH 2) 2 -CH 2). -, R = CHPh2) and II (R3, R4 = -CH2- (CH2) 3CH2-, R = CHPh2), respectively. These diesters are selectively hydrolyzed as in Example 6 to give the corresponding prodrug ester acids (II) (R = H).

Claims (2)

A process for the preparation of therapeutically useful 7-amino-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido [2,1-a] [2] benzazepine-4 carboxylic acid derivatives of formula (II) and pharmaceutically acceptable salts thereof; 10 R'iOOC \ CH, i j-n j (ii <b ^ hn / li Y> Which formula R 'is hydrogen, C 1-6 alkyl or diphenylmethyl; R'x is hydrogen or C1-6 alkyl; and R 2 is hydrogen or phenyl-C 25. In 292 NJ (XXII) HJT u COOR '30 is reacted with a reagent of formula (A) COOR'-I 2 other than hydrogen, in the presence of a base, and if desired, one or both of the ester groups R 'and R' are removed 2. A process according to claim 1, characterized in that [4a, 7a (R *), 126] - 7 - [[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1,2 is prepared. , 3,4,6,7, 12b-octahydro-6-oxopyrido [2,1-a] [2] benzazepine-4-carboxylic acid.