MXPA05014056A

MXPA05014056A - Process for the preparation of nonpeptide substituted spirobenzoazepine derivatives

Info

Publication number: MXPA05014056A
Application number: MXPA/A/2005/014056A
Authority: MX
Inventors: Xiaohu Deng; Birdella Kenney; Jimmy T Liang; Neelakandha Mani; Frank J Villani; Fan Zhangplasket; Hua Zhong
Original assignee: Xiaohu Deng; Birdella Kenney; Jimmy T Liang; Neelakandha Mani; Frank J Villani; Fan Zhangplasket; Hua Zhong
Priority date: 2003-06-17
Filing date: 2005-12-19
Publication date: 2006-10-17

Abstract

Novel spirobenzoazepine compounds, novel processes for the preparation of nonpeptide substituted spirobenzoazepine dervatives, and novel processes for the preparation of intermediates in the preparation of such derivatives. Novel intermediates in the preparation of nonpeptide substituted spirobenzoazepine derviatives.

Description

PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF NONPEPTIDATED REPLACED ESPIROBENZOAZEPINA FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of substituted non-peptide spirobenzoazepine derivatives and to novel processes for the preparation of intermediates in the preparation of said derivatives. The present invention also relates to novel intermediates in the preparation of substituted non-peptide spirobenzoazepine derivatives.

BACKGROUND OF THE INVENTION The present invention relates to a novel process for the preparation of substituted spirobenzoazepine non-peptide derivatives useful for treating and / or preventing conditions involving increased vascular resistance and heart failure. Particularly, substituted non-peptide spirobenzoazepine derivatives are useful in the treatment and / or prevention of disorders such as aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure / heart failure, coronary vasospasm, cardiac ischemia, liver cirrhosis, vasospasm renal, renal deficiency, edema, ischemia, stroke, thrombosis, water retention, nephritic syndrome and central nervous system lesions. Chen et al., In PCT publication WO 02/02531 describe a process for the preparation of substituted non-peptide spirobenzoazepines. However, this process requires the use of an explosive reagent, cryogenic temperature and chromatographic purifications, and therefore, it is not advisable for the commercial preparation of said compounds.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of compounds of formula (I) wherein it is selected from the group consisting of aryl and heteroaryl; provided that the heteroaryl group does not contain a nitrogen atom; a is an integer from 1 to 3; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, phenyl, substituted phenyl, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulphone; -R2-R3- is selected from the group consisting of ~ ~ N CH2- -y R10 is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, and - (B) o-r G-ÍEÍo-HW) ^; wherein B is selected from (CH2)? - 3. NH or O; G is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl; E is selected from -O-, -S-, -NH-, - (CH2) 0-3-N (R11) C (O) - or - (CH2) or -3-C (O) NR11-; wherein R11 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; each W is independently selected from hydrogen, alkyl, substituted alkyl, amino, substituted amino, alkylthiophenyl, alkyl sulphoxydiphenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; X is selected from the group consisting of CH, CH2, CHOH and CO); r r_ represents a double or single link; with the proviso that when R1 is iodo, bromo alkylthio, arylthio, alkyl sulfone or aryl sulphone, then ===== is a double bond; n is an integer from 1 to 3; b is an integer from 1 to 2; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, phenyl and substituted phenyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aldehyde, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, - (CH2) kNZ1Z2 and-C (O) NZ1Z2; where k is an integer from 1 to 4; Z1 and Z2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aminocarbonyl or substituted aminocarbonyl; alternatively Z1 and Z2 are taken together with the N atom to which they are attached to form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; or an optical isomer, enantiomer, diastereomer, racemate thereof or a pharmaceutically acceptable salt thereof; which comprises reacting a compound of formula (II) wherein -R, 2a-DR3a - is selected from the group consisting of -NH-CH2- and -CH2-NH- with a compound of formula (XV), wherein T1 is Cl, Br or F; in the presence of a base capable of neutralizing HT1; in a non-alcoholic organic solvent or a mixture of a non-alcoholic organic solvent and water, to produce the corresponding compound of formula (I). The present invention also relates to a process for the preparation of a compound of formula (II) where is selected from the group consisting of aryl and heteroaryl; with the proviso that the aryl does not contain a nitrogen atom; a is an integer from 1 to 3; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, phenyl, substituted phenyl, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulphone; -R2a-R3a- is selected from the group consisting of -NH-CH2- and -CH2-NH-X is selected from the group consisting of CH, CH2, CHOH and CO); ===== represents a double or single link; with the proviso that when R1 is iodo, bromo alkylthio, arylthio, alkyl sulfone or aryl sulphone, then ===== is a double bond; n is an integer from 1 to 3; b is an integer from 1 to 2; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, phenyl and substituted phenyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aldehyde, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, - (CH2) kNZ1Z2 and -C (O) NZ1Z2; where k is an integer from 1 to 4; Z1 and Z2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aminocarbonyl or substituted aminocarbonyl; alternatively Z1 and Z2 are taken together with the N atom to which they are attached to form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof; which comprises reacting a compound of formula (VII), where p is an integer from 0 to 1, q is an integer from 1 to 2, with the proviso that when p is 0, then q is 2 and when p is 1 then q is 1, PG1 is a nitrogen protecting group and A2 is lower alkyl, with a compound of formula (VIII) wherein Q2 is a leaving group and A3 is lower alkyl; in the presence of a base capable of deprotonating an alpha proton to the ketone in the compound of formula (VII); in an aprotic solvent, to produce the corresponding compound of formula (IX); reducing the compound of formula (IX) to produce the corresponding compound of formula (X); (X) (XI) reacting the compound of formula (X) in the presence of a base capable of deprotonating an alpha proton to the CO2A3 substituent; in an organic solvent that does not prevent the deprotonation of an alpha proton to the C02A3 substituent, to produce the corresponding compound of formula (xi); reducing the compound of formula (XI) to produce the corresponding compound of formula (Xll); reacting the compound of formula (Xll) to produce the corresponding compound of formula (II). The present invention also relates to a process for the preparation of compounds of formula (XVa) wherein T3 is selected from the group consisting of Cl, Br and F; G is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl; W is selected from hydrogen, alkyl, substituted alkyl, amino, substituted amino, alkylthiophenyl, alkyl sulfoxydiphenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; which comprises reacting a compound of formula (XX), wherein A4 is lower alkyl with a compound of formula (XXI) wherein T2 is Cl, Br or F; in the presence of a base capable of neutralizing HT2, in a non-alcoholic organic solvent or in a mixture of non-alcoholic organic solvent and water, to produce the corresponding compound of formula (XXII); (X lll) hydrolyzing the compound of formula (XXII), to produce the corresponding compound of formula (XXlll); (XVa) reacting the compound of formula (XXIII) with a reagent capable of converting the substituent -C02H to the corresponding substituent -C (0) T3; in an inert organic solvent, to produce the corresponding compound of formula (XVa). The present invention further relates to a compound of formula (II) where is selected from the group consisting of aryl and heteroaryl; with the proviso that the heteroaryl does not contain a nitrogen atom; a is an integer from 1 to 3; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, phenyl, substituted phenyl, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone; -R2a-R3a- is selected from the group consisting of -NH-CH2- and _CH2-NH-; X is selected from the group consisting of CH, CH2, CHOH, and C (O); = z represents a single or double bond, with the proviso that when R1 is iodo, bromo, alkylthio, aryl, alkyl sulfone or aryl sulphone, then _____: is a double bond; n is an integer from 1 to 3; b is an integer from 1 to 2; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, phenyl and substituted phenyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aldehyde, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, - (CH2) kNZ1Z2 and -C (O) NZ1Z2; where k is an integer from 1 to 4; Z1 and Z2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aminocarbonyl or substituted aminocarbonyl; alternatively Z1 and Z2 are taken together with the N atom to which they are attached to form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof. The present invention further relates to a process for the preparation of (4R) -1, 2,3,5-tetrahydro-spiro [4 - / - 1-benzazepin-4,1 '- [2] cyclopenten] -3 acid The carboxylic acid comprising reacting a racemic mixture of 1, 2,3,5-tetrahydro-spiro [4 / - / - 1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid with acid (-) - camphorsulfonic. The present invention also relates to a process for the preparation of (4S) -1, 2,3,5-tetrahydro-spiro [4 / -1-benzazepin-4,1l- [2] cyclopenten] -3 ' -carboxylic comprising reacting a racemic mixture of 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid with (+) - camphorsulfonic. The present invention also relates to novel salts of (4R) -1 - [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spyr [[ 4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid, a compound of formula (Ia) (the) In particular, the present invention relates to salts of diethylamine, piperazine, and (4R) -1- [4- (2-cyoro-5-fluorobenzoyl) amino-3-methoxybenzoyl 1- (2-hydroxyethyl) pyrrolidine. ] -1, 2,3,5-tetrahydro-spyrro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid. The present invention also relates to novel processes for the preparation of the novel crystalline salts of the compounds of formula (la). The present invention also relates to a compound prepared according to any of the methods described herein. To illustrate the invention, mention is made of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound prepared according to any of the methods described herein. An illustration of the invention is a pharmaceutical composition made by mixing a compound prepared according to any of the methods described herein and a pharmaceutically acceptable carrier. The invention is illustrated with a process for making a pharmaceutical composition comprising mixing a compound prepared according to any of the methods described herein and a pharmaceutically acceptable carrier. Another example of the invention is the use of a compound prepared according to any of the methods described herein in the preparation of a medicament for treating at least one of: (a) aggression, (b) obsessive-compulsive disorders, (c) hypertension, (d) dysmenorrhea, (e) congestive heart failure / heart failure, (f) coronary vasospasm, (g) cardiac ischemia, (h) liver cirrhosis, (i) renal vasospasm, (j) renal impairment, (k) edema, (I) ischemia, (m) stroke, (n) thrombosis, (or) water retention, (p) nephritic syndrome and (q) central nervous system lesions , in a subject that needs it.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of compounds of formula (I) wherein, n, b and R are as defined herein. The compounds of formula (I) interrupt the binding of the peptide hormone vasopressin to its receptors and are therefore useful for treating conditions involving increased vascular resistance and heart failure. In particular, the compounds of formula (I) are useful in the treatment and / or prevention of disorders such as aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure / heart failure, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal deficiency, edema, ischemia, stroke, thrombosis, water retention, nephritic syndrome and central nervous system lesions. The present invention also relates to a process for the preparation of compounds of formula (II) wherein, n, b and R4 are as defined herein. The compounds of formula (II) are useful as intermediates in the preparation of compounds of formula (I). The present invention also relates to a process for the preparation of compounds of formula (XVa) where T3, G and W are as defined herein. The compounds of formula (XVa) are useful as intermediates in the preparation of compounds of formula (I). The present invention further relates to compounds of formula (II) wherein R, n, b, and R 4 are as defined herein. The compounds of formula (II) are useful as intermediates in the preparation of compounds of formula (I). The present invention further relates to a process for the preparation of the acid (4R) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'- carboxylic comprising reacting a racemic mixture of 1, 2,3,5-tetrahydro-spiro [4/1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid with (-) acid -canforsulfonic. In one embodiment of the present invention, the (-) - camphorsulfonic acid is present in an amount greater than or equal to about one equivalent, preferably about one equivalent. The present invention further relates to a process for the preparation of (4S) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4, T- [2] cyclopenten] -3l-carboxylic acid. co comprising reacting a racemic mixture of the acid I ^. Sd-tetrahydro-spiro ^ Hl-benzazepin ^ .l '- [2] cyclopenten] -3'-carboxylic acid with (-) - camphorsulfonic acid. In one embodiment of the present invention, the (-) - camphorsulfonic acid is present in an amount greater than or equal to about one equivalent, preferably about one equivalent. The present invention also relates to novel salts of (4R) -1 - [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro acid [4H-] 1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid, the compound of formula (la). (the) In particular, the present invention relates to salts of diethylamine, piperazine, and (4R) -1 - [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl 1- (2-hydroxyethyl) pyrrolidine. ] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 2] cyclopenten] -3'-carboxylic acid. Preferably, the salts of diethylamine, piperazine and 1- (2-hydroxyethyl) pyrrolidine of the compound of formula (la) are crystalline.

The present invention also relates to a product prepared according to any of the methods described herein. One embodiment of the present invention is a process for the preparation of a compound of formula (I) wherein. , is phenyl, X is -CH2-, R5 is -CO2H, n is 1, b is 0, -R2-R3- is and R10 is - (3-methoxy-phenyl) -4- (NH-C (O) - (2-chloro-5-fluoro-phenyl)). Another embodiment of the present invention is a process for the preparation of a compound of formula (II) wherein is phenyl, X is -CH2-, R5 is -CO2H, n is 1, b is 0, and -R2a-R3a- is -NH-CH2-. Even another embodiment of the present invention is a process for the preparation of a compound of formula (XVa) wherein T3 is Cl, G is 1- (3-methoxy-phenyl) and W is 1- (2-chloro-5-fluoro-phenyl). Another embodiment of the present invention is a compound of formula (II) wherein (I) is phenyl, X is -CH2-, R5 is -CO2H, n is 1, b is 0, and -R2a-R3a- is - NH-CH2- Even another embodiment of the present invention is a compound of formula (II) selected from the group consisting of a racemic mixture of 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin- 4,1 '[2] cyclopenten] -3, -carboxylic acid (4R) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1' - [2] cyclopenten] -3 '-carboxylic; (4S) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4-1 '- [2] cyclopenten] -3'-carboxylic acid and pharmaceutically acceptable salts thereof. Another embodiment of the present invention is 4- (2-chloro-5-fluoro-benzoylamino) -3-methoxy-benzoyl chloride. The term "halogen" should include iodine, bromine, chlorine and fluorine. Unless otherwise indicated, "alkyl" and "alkoxy" as used herein, whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, as well as cycloalkyl groups containing 3 to 8 carbons in the ring and preferably 5 to 7 carbons in the ring, or any number within these scales. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2- methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Unless otherwise indicated, "lower" when used with alkyl, shall mean a carbon chain of 1 to 4 carbon atoms. Alkoxy radicals are oxygen ethers formed from straight-chain, branched or cyclic alkyl groups previously described. An alkyl as used herein may be substituted, for example, with amino, substituted amino, halogen, hydroxy, heterocyclyl, substituted heterocyclyl, alkyl, alkoxy, alkoxycarbonyl, heteroaryl, substituted heteroaryl, and / or aryl such as phenyl or benzyl . "Heterocyclyl" or "heterocycle" is a single or saturated saturated or partially saturated ring system of 3 to 8 elements comprising carbon atoms and one to three heteroatoms selected from N, O and S. As used herein, "heterocyclyl" or "heterocycle" also refers to an unsaturated single or fused ring system of 3, 4, 7, or 8 elements which comprises carbon atoms and from one to three heteroatoms selected from N, O and S. Heterocyclyl group can be attached to any hetero atom or carbon atom which results in the creation of a stable structure. Examples of heterocyclyl groups include but are not limited to pyridine, pyrimidine, oxazoline, pyrrole, imidazole, morpholine, furan, indole, benzofuran, pyrazole, pyrrolidine, piperidine, and benzimidazole. "Heterocyclyl" or "heterocycle" may be substituted with one or more independent groups including, but not limited to H, halogen, oxo, OH, alkyl, substituted alkyl, amino, heteroaryl, aldehyde, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylcarboxyl , alkoxy, and -NZ1Z2 wherein Z1 and Z2 are as described above. The term "Ar" or "aryl" as used herein, whether used alone or as part of a substituent group, refers to an aromatic group such as phenyl and naphthyl. In addition, "Ph" or "PH" denotes phenyl. When the Ar or aryl group is substituted, it may have one to three substituents which are independently selected from Ci-Cs alkyl, Ci-Cs alkoxy, aralkoxy, substituted C?-C8 alkyl (eg, trifluoromethyl) , fluorocarbon (for example, trifluoromethoxy) alkoxy, halogen, cyano, hydroxy, nitro, optionally substituted amino, carboxyl, alkylcarboxyl, alkoxycarbonyl, C 1 -C 4 alkylamino (ie, -NH-C alquilo alkyl) C), C 1 -C 4 dialkylamino (ie, -N- [C 1 -C 4 alky] wherein the alkyl groups may be the same or different), -O (CO) O-alkyl, -O- heterocyclyl optionally substituted with alkyl or alkylcarbonyl optionally substituted (for example, _o ° -AV? _y -J), optionally substituted heteroaryl (e.g., and optionally substituted with a group selected from alkyl, substituted alkyl, aldehyde, alkylcarbonyl, carboxyl, alkylcarboxyl, alkoxycarbonyl, and -NZ1Z2 wherein Z1 and Z2 are as previously described) and unsubstituted phenyl , mono-, di- or tri-substituted wherein the substituents on the phenyl are independently selected from aryl, C?-C8 alkyl, C -?-C8 alkoxy, substituted Ci-Cs alkyl, C alco alkoxy -? - Fluorinated C8, halogen, cyano, hydroxy, amino, nitro, carboxyl, alkylcarboxyl, alkylamino, dialkylamino and heteroaryl. The term "heteroaryl" as used herein represents a stable monocyclic aromatic ring system of five or six elements or aromatic bicyclic of nine to ten elements or benzo-fused which comprises carbon atoms and from one to three heteroatoms selected from N, O and S. The heteroaryl group may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl. , indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazole or quinolinyl. Preferred heteroaryl groups include pyridinyl, thiophenyl, furanyl and quinolinyl. When the heteroaryl group is substituted, the heteroaryl group may have one to three substituents which are independently selected from C 1 -C 8 alkyl, substituted C 1 -C 8 alkyl, halogen, aldehyde, alkylcarbonyl, aryl, heteroaryl, alkoxy , alkylamino, dialkylamino, arylamino, nitro, carboxyl, alkylcarboxyl, and hydroxy. The term "aralkoxy" denotes an alkoxy group substituted with an aryl group (for example, benzyloxy). The term "Ac" as used herein, whether used alone or as part of a substituent group, means acetyl. The terms "substituted alkylcarboxy", "substituted amino" and "substituted aminocarbonyl" denote the substitution of said groups with at least one element selected from halogen, alkyl, substituted alkyl, aryl, alkoxy, amino or substituted amino. Whenever the term "alkyl" or "aryl" or any of its prefix roots appear in a name of a substituent (eg, aralkyl, dialkylamino), it shall be construed as including those limitations given above for "alkyl" and "aryl" . The designated numbers of carbon atoms (eg, C-i-Cß) will independently refer to the number of carbon atoms in an alkyl or cycloalkyl portion or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. It is intended that the definition of any substituent or variable in a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns in the compounds of this invention can be selected by one skilled in the art to provide compounds that are chemically stable and that can be easily synthesized by known techniques, as well as those methods discussed herein. To provide a more concise description, some of the quantitative expressions given herein are not qualified by the term "approximately". It is understood that if the term "approximately" is used explicitly or not, each quantity given herein is meant to refer to the given actual value, and also intends to refer to the approximation to said value given that it is reasonably inferred based on the expert in the technique, including approximations originated by the experimental and / or measurement conditions for said given value. As used in this, unless otherwise indicated, the term "aprotic solvent" shall mean any solvent that does not produce a proton. Suitable examples include but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like. As used herein, unless otherwise indicated, the term "leaving group" shall mean a charged or uncharged atom or group which is exited during a substitution or displacement reaction. Suitable examples include, but are not limited to Br, Cl, L, mesylate, tosylate, and the like. As used herein, unless otherwise indicated, the term "nitrogen protecting group" shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which can be easily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to, carbamates - groups of the formula -C (O) OR where R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2 = CH-CH2-, and the like; amides - groups of the formula -C (O) -R 'wherein R' is for example methyl, phenyl, trifluoromethyl and the like; N-sulfonyl derivatives - groups of the formula -SO 2 -R "wherein R" is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6- trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups can be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

The term "subject" as used herein, refers to an animal, preferably a mammal, preferably a human, which is or has been the object of treatment, observation or experiment. As used herein, "treating" a disorder means eliminating or otherwise improving the cause and / or effects thereof, "inhibiting" or "inhibiting" the onset of a disorder means preventing, slowing or reducing the likelihood of said beginning. As used herein, the term "composition" is intended to encompass a product that comprises the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Methods are known in the art for determining therapeutically and prophylactically effective doses for the present pharmaceutical composition. The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that produces the biological or medicinal response in a tissue, animal or human system that is sought by a researcher, veterinarian, doctor or other physician. , which includes relief of the symptoms of the disease or disorder being treated. The term "prophylactically effective amount" refers to that amount of active compound or pharmaceutical agent that inhibits in a subject the onset of a disorder sought by a researcher, veterinarian, doctor or other physician, the delay of said disorder is mediated by the reduction of increased bascular resistance. Under the standard nomenclature used throughout this description, the terminal portion of the designated side chain is first described, followed by functionality adjacent to the point of attachment. Thus, for example, a substituent "phenylalkylaminocarbonyl-CrC6-alkyl-CrCe" refers to a group of the formula As used herein, in compounds of formula (VIII) (HIV) it is intended that the R4 groups can be attached to any of the carbon atoms comprising the alkyl portion of the compound of formula (VIII). Therefore, the R4 groups can not be attached to any of the atoms of Q2 of the CO2A3 portions of the compound of formula (VIII). This structural designation of the R4 groups should also extend to compounds of formula (IX) and compounds of formula (X).

The following are the abbreviations used in the specification, particularly the diagrams and examples: The compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt or salts. For use in medicine, the salt or salts of the compounds of this invention refers to "non-toxic" pharmaceutically acceptable salts or salts. However, other salts may be useful in the preparation of compounds according to this invention or their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethane sulfonic, benzenesulfonic acid , oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexansulfamic, salicylic, saccharinic or trifluoroacetic. Representative basic / cationic salts include, but are not limited to benzathine, chloroprocaine, choline, dietalonamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc. When the compounds according to this invention are chiral, including those containing at least one stereogenic center, they can accordingly exist as enantiomers. When the stereogenicity extends to a plurality of molecular regions, including cases where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. It will also be understood that all such isomers and mixtures thereof are covered within the scope of the present invention. In addition, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and said solvates are also intended to be encompassed within the scope of this invention.

When the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques, such as resolution, for example by diastereomeric salt formation, kinetic resolution including variants of the same, such as dynamic resolution, preferential crystallization, biotransformation, enzymatic transformation and preparative chromatography. The compounds can be prepared in racemic form, or the individual enantiomers can be prepared either by enantiospecific synthesis or by resolution. For example, the compounds can be reduced in component enantiomers through standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-) - di-p-toluoyl-D- acid. tartaric and / or (+) - di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds can also be reduced by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be separated using a chiral HPLC column. During any of the procedures for the preparation of the compounds of the present invention, it may be necessary and / or advisable to protect sensitive or reactive groups in any of the molecules involved. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups In Organic Chemistry, ed. J.F: W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups can be removed at a convenient subsequent stage using methods known in the art. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo to the required compound. Thus, in the methods of treatment of the present invention, the term "administration" could include the treatment of the various disorders described with the specifically described compound or with a compound that can not be specifically described, but which is converted to the compound specified live after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Desing of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. The present invention relates to a process for the preparation of compounds of formula (II) as shown in scheme 1.

SCHEME 1 (IX) (X) (Xi) (XIO (XIIO (XIV) Accordingly, a suitably substituted compound of formula (III), wherein A1 is a lower alkyl and wherein p is an integer from 0 to 1, a known compound or compound prepared by known methods, it reacts with a suitable protective reagent, under known conditions, to produce the corresponding compound of formula (IV), wherein PG1 is the corresponding nitrogen protecting group, for example, when the protective reagent is Boc anhydride, CBz chloride, tosyl or Mtr chloride, then PG1 is BOC, CBz, Tosyl or Mtr, respectively, preferably when p is 0, then PG1 is selected from tosyl, BOC, CBz or Mtr, more preferably, PG1 is tosyl. Preferably, when p is 1, then PG1 is selected from BOC, CBz or Mtr. The compound of formula (IV) reacts with an appropriately substituted compound of formula (V), wherein A2 is a lower alkyl, Q1 is a leaving group such as a Br, Cl, I, tosylate, mesylate, and the like and when in the compound of formula (IV) p is 0 then q is 2 and when in the compound of formula (IV) p is 1 then q is 1, a known compound or compound prepared by known methods, in the presence of an inorganic base such as K2CO3, Na2CO3, CS2CO3, and the like, and mixtures thereof, or a tertiary amine base such as pyridine, TEA, DIPEA and the like, and mixtures thereof in an aprotic polar solvent such as DMF, dioxane, THF, and acetonitrile and the like, and mixtures thereof, to produce the corresponding compound of formula (VI).

The compound of formula (VI) is subjected to ring closure, in the presence of a base such as a sodium or potassium alkoxide (such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, ethoxide potassium, potassium t-butoxide and the like, and mixtures thereof), LDA, lithium hexamethyldisilizone, and the like in an organic solvent such as toluene, THF, t-butanol, and the like, and mixtures thereof , to produce the corresponding compound of formula (VII).

The compound of formula (VII) reacts with an appropriately substituted compound of formula (HIV), wherein A3 is a lower alkyl, Q2 is a suitable leaving group such as Br, Cl, I, tosylate, mesylate, and the like, and wherein n is an integer from 1 to 3, a known compound or a compound prepared by known methods, in the presence of a base capable of deprotonating an alpha proton to the ketone in the compound of formula (VII), such as a base inorganic such as K2CO3, Na2CO3, Cs2CO3, and the like, and mixtures thereof, or an organic tertiary amine base such as pyridine, TEA, DIPEA, and the like, and mixtures thereof, or an alkali metal alkoxide such such as sodium t-butoxide, potassium t-butoxide, sodium methoxide, and the like, and mixtures thereof in an aprotic solvent such as DMF, dioxane, THF, acetonitrile, and the like, and mixtures thereof, for produce the corresponding compound of formula (IX). The compound of formula (IX) is reduced with a suitable reducing agent such as trimethylsilane, triethylsilane, LAH, borane complex THF, and the like, in the presence of a Lewis acid such as BF3"etherate, titanium tetrachloride, and the like. similar, optionally in the presence of an acid such as TFA, methanesulfonic acid, trifluoromethanesulfonic acid (triflic acid), and the like, and mixtures thereof, in a halogenated organic solvent such as dichloroethane, dichloromethane, and the like, and mixtures thereof. them, to produce the corresponding compound of formula (X). In one embodiment, the compound of formula (IX) is reduced by reaction with triethylsilane in the presence of BF3 * etherate, TFA and methanesulfonic acid. For example, the compound of formula (IX) is reduced by reaction with triethylsilane in the presence of BF3 * etherate, TFA and methanesulfonic acid, wherein triethylsilane, BF3 * etherate, TFA and methanesulfonic acid are present in a molar ratio of 3.75 to 2.79 to 5.27 to 1.2, respectively. In another example, triethylsilane, BF3 * etherate, TFA and methanesulfonic acid are present in a molar ratio of 5.0 to 1.8 to 2.5 to 6.0, respectively. Alternatively, the compound of formula (XI) is reduced by reaction with hydrogen gas, in the presence of a catalyst such as Pd on carbon, PtO2, Raney Nickel, and the like, in the presence of a Bronsted acid such as acetic acid , sulfuric acid, and the like, in an organic alcohol solvent such as methanol, ethanol, and the like, and mixtures thereof, to produce the corresponding compound of formula (X). Preferably, the reducing agent preferably reduces and deoxygenates the -C (O) - to a -CH2- on the reduction of the ester group -CO2A2 and / or CO2A3.

The compound of formula (X) is subjected to ring closure, in the presence of a base capable of deprotonating an alpha proton to the C02A3 substituent such as an alkali metal alkoxide (e.g. sodium or potassium such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, and the like, and mixtures thereof), LDA, lithium hexamethyldisilizone, and the like, in an organic solvent that does not prevent deprotonation of an alpha proton to the CO2A3 substituent such as toluene, THF, t-butanol, and the like, and mixtures thereof, preferably in an aprotic organic solvent such as THF, toluene, and the like and mixtures thereof, to produce the corresponding compound of the formula (XI). The compound of formula (XI) is reduced with a suitable reaction agent such as, for example, sodium borohydride., diisobutyl aluminum hydride (DiBAL-H), and the like, in an organic solvent such as ethanol, methanol, THF, and the like, and mixtures thereof, to produce the corresponding compound of formula (Xll). Alternatively, the compound of formula (XI) is reduced by reaction with hydrogen gas, in the presence of a catalyst such as Raney Nickel, and the like, in an alcoholic organic solvent such as methanol, ethanol, and the like, and mixtures thereof. them, to produce the corresponding compound of formula (Xll).

Preferably, the reducing agent preferably reduces and deoxygenates the -C (O) - a -CH (OH) - by reducing the ester group C02A3 The compound of formula (Xll) reacts according to known methods, to produce the corresponding compound of formula (XIII). More particularly, the compound of formula (Xll) is converted to the compound of formula (XIII) by using one or more steps to (a) hydrolyse the ester -CO2A3 to the corresponding -CO2H, for example by reaction with water, catalyzed with an acid strong as H2SO4, HCl and the like or mixtures thereof; or through the reaction with water, catalyzed with a strong base such as NaOH, LiOH, KOH, and the like, and mixtures thereof, (b) dehydrating to form a conjugated double bond, for example by reaction with an acid strong such as H2SO4, HCl, and the like and mixtures thereof; or by reaction with mesyl chloride in the presence of an organic base such as DBU, DMAP, TEA, pyridine, and the like, and mixtures thereof, and (c) deprotecting the -N-PG1 group to the corresponding -NH, for example by reaction with a strong acid such as H2SO4, HCl and the like, and the like, and mixtures thereof; or when PG1 is CBz, by hydrogenation with hydrogen gas, in the presence of a suitable catalyst such as Pd on carbon. A person skilled in the art will recognize that the above steps can be performed in any order in which they produce the corresponding compound of formula (XIII).

Preferably, the protecting group PG1 is a protecting group that can be removed under acidic conditions and the compound of formula (Xll) reacts to produce the compound of formula (XIII) in one step, by reacting the compound of formula (Xll) with a strong acid (ie, an acid capable of performing dehydration to a conjugated double bond, deprotection of nitrogen and hydrolysis of the ester to the carboxylic acid in the compound of formula (Xll)), such as sulfuric acid, hydrochloric acid, and the like and mixtures thereof, in a polar organic solvent such as acetic acid, and the like, preferably at an elevated temperature on the scale from about room temperature to about 140 ° C, more preferably about 100 ° C, to produce the corresponding compound of formula (XIII). Alternatively, the compound of formula (XII) reacts with an acid of Eaton to produce the compound of formula (XIII). The compound of formula (XIII) is optionally reduced using hydrogen gas or a suitable source of hydrogen such as triethylsilane, dimethylphenylsilane, HCOONH4, in the presence of a suitable catalyst such as Pd on carbon, Raney Nickel, Rh (P (C6H5) 3) 3, Pt02, RhCl (P (C6H5) 3) 3, and the like, and mixtures thereof in an organic solvent such as ethyl acetate, THF, methanol, ethanol, and the like, and mixtures thereof, to produce the corresponding compound of formula (XIV). Alternatively, the compound of formula (XIII) may optionally react with sodium borohydride, in an organic solvent such as methanol, THF, and the like, and mixtures thereof, to produce the corresponding compound of formula (XIV). A person skilled in the art will recognize that compounds of formula (XI) can be deprotected and optionally hydrolyzed by known methods (e.g., as described above), to produce the corresponding compound of formula (II) wherein R5 is alkoxycarbonyl or carboxylic acid and X is C (O). The compounds of formula (Xll) can be deprotected and optionally hydrolyzed (e.g., as described above), to yield the corresponding compound of formula (II) wherein R5 is alkoxycarbonyl or carboxylic acid and X is CHOH. A person skilled in the art will recognize that compounds of formula (XIII) correspond to compounds of formula (II) wherein R5 is carboxyl or alkoxycarbonyl and X is CH. Similary, compounds of formula (XIV) correspond to the compounds of formula (II) wherein R5 is carboxyl or alkoxycarbonyl and X is CH2. A person skilled in the art will further recognize that compounds of formula (II) wherein R5 is different from alkoxycarbonyl or carboxyl, can be prepared from the corresponding compound of formula (II) wherein R5 is carboxyl by known methods. Preferably, the compound of formula (II) is reduced in its corresponding enantiomers (when == is a double bond) or diastereomers (when rrr = is a single bond) by known methods, for example by chromatography of column, selective recrystallization or by resolution with a suitable resolving agent such as (-) - camphorsulfonic acid, (+) - camphorsulfonic acid, D-tartaric acid or L-tartaric acid, and the like. One skilled in the art will recognize that when the compound of formula (II) is a mixture of enantiomers, the enantiomers can be separated using classical resolution or through selective recrystallization first through converting the enantiomers into diastereomers using a chiral auxiliary followed by recrystallization selective or column chromatographic separation of the diastereomers and regeneration of the original enantiomers. The present invention also relates to a process for the preparation of compounds of formula (I) as shown in scheme 2.

SCHEME 2 Accordingly, a suitably substituted compound of formula (II), a compound prepared as shown in scheme 1 above, reacts with a suitable substituted compound of formula (XV), wherein T 1 is Cl, Br, or F, preferably, T1 is Cl, a known compound or a compound prepared by known methods, in the presence of a base capable of neutralizing HT1; preferably, the base capable of neutralizing HT1 does not react with the compound of formula (XV), such as an organic tertiary amine base such as TEA, DIPEA, pyridine, and the like or an inorganic base such as K2CO3, Na2HCO3, NaOH, KOH , and the like, in a non-alcoholic organic solvent such as THF, dichloroethane, dichloromethane, toluene, pyridine, and the like to a mixture of a non-alcoholic organic solvent and water such as a THF / water mixture, and the like, wherein said mixture can be biphasic, preferably at a temperature in the range of between about 0 ° C and close to room temperature, to produce the corresponding compound of formula (I). One skilled in the art will recognize that when in the compound of formula (II) R5 is carboxyl or another reactive group, the carboxyl group or reagent is preferably protected prior to the reaction with the compound of formula (XV) and the protecting group removed afterwards. of the reaction with the compound of formula (XV), to produce the corresponding compound of formula (I). For example, where the group R5 is carboxyl, the carboxyl can be protected by reaction of the corresponding compound of formula (II) with TMSCI in situ; or the carboxyl can be protected as a lower alkyl ester. One skilled in the art will also recognize that when the compound of formula (I) R5 is carboxyl or alkoxycarbonyl, the compound of formula (I) may optionally also be reacted according to known methods to transform the R5 carboxyl or alkoxycarbonyl group to alkyl, alkyl substituted, aldehyde, substituted alkoxycarbonyl, - (CH2)? < NZ1Z2 or -C (O) NZ1Z2. Alternatively, the compounds of formula (I) can be prepared by reacting the compound of formula (III) with a suitably substituted acid halide, a compound of the formula (XV) In the presence of a base such as TEA, DPEA, pyridine, and the like, and mixtures thereof, in an aprotic organic solvent such as THF, dichloroethane, dichloromethane, toluene, pyridine and the like, and mixtures thereof, to produce the corresponding compound of formula (IV) wherein the substituent -C (O) -R10 is the group PG1, a compound of the formula The compound of formula (IVa) can then be reacted according to the procedure presented in scheme 1 to produce the corresponding compounds of formulas (VI), (Vil), (IX), (X), and (Xll) wherein the substituent -C (O) -R10 is the group PG1. The compounds of formula (XV) wherein R10 is -GEW and wherein G is as defined above, E is -NH-C (O) - and W is selected from the group consisting of alkyl, substituted alkyl, amino, amino substituted, alkylthiophenyl, alkylsulfoxyphenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; they can be prepared according to the procedure presented in scheme 3.

SCHEME 3 Accordingly, a suitably substituted compound of formula (XX), wherein A4 is lower alkyl, a known compound or compound prepared by known methods, reacts with an appropriately substituted compound of formula (XXI) wherein T2 is Cl, Br or F, preferably T2 is Cl, a known compound or compound prepared by known methods, in the presence of a base capable of neutralizing HT2; preferably the base capable of neutralizing HT2 does not react with the compound of formula (XV), such as an organic tertiary amine base such as TEA, DIPEA, pyridine, and the like, and mixtures thereof, or an inorganic base such as K2CO3 , Na2CO3, NaHCO3, NaOH, KOH, and the like, and mixtures thereof, in a non-alcoholic organic solvent such as ethyl acetate, THF, methylene chloride, dichloroethane, dichloromethane, toluene, benzene, pyridine, and the like, and mixtures thereof, or a mixture of a non-alcoholic organic solvent and water such as a THF / water mixture, and the like, wherein said mixture may be biphasic, preferably at a temperature in the range of about 0 ° C. and near ambient temperature, to produce the corresponding compound of formula (XXII). The compound of formula (XXII) is hydrolyzed through the reaction with water in the presence of a base such as NaOH, KOH, LiOH, and the like, and mixtures thereof in an organic solvent such as methanol, ethanol, THF, dioxane and the like, and mixtures thereof, to produce the corresponding compound of formula (XXIII). The compound of formula (XXlll) reacts with a reagent capable of converting -C02H (carboxyl group) to the corresponding -C (0) T3 (ie, an acid halide group such as -C (0) CI, -C (0) ) Br or -C (O) F), such as oxalyl chloride, thionyl chloride, thionyl bromide, phosphorous tribromide, SF4 cyanuric fluoride, and the like, preferably oxalyl chloride, in an inert organic solvent such as DCM, DCE, toluene, and the like, preferably at a temperature in the range of between about 0 ° C and close to room temperature, to produce the corresponding compound of formula (XVa), wherein T 3 is the corresponding halide anion. For example, when the compound of formula (XXIII) reacts with an oxalyl chloride, T3 is Cl. One skilled in the art will recognize that when a reaction step of the present invention can be carried out in a variety of solvents or solvent systems, The reaction step can also be carried out in a mixture of suitable solvents or solvent systems. The present invention also relates to novel salts of (4f?) - 1 - [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro acid [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid (the compound of formula (la)). More specifically, the present invention relates to diethylamine, piperizine and 1- (2-hydroxyethyl) -amino-3-methoxybenzoyl] -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-hydroxyethyl) pyrrolidine acid salts , 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4, r- [2] cyclopenten] -3'-carboxylic acid. X-ray powder diffraction patterns for the salts of the present invention are measured as follows. The salt sample is then loaded into a conventional X-ray mount and analyzed as soon as it is received. Using an X-Celerator detector, the sample is scanned from 3 to 35 ° 2T at a step size of 0.0165 ° 2T and a time per step of 10.16 seconds. The effective scanning speed is 0.20677s. The following 45 kV and 40 mA instrument voltage and current settings are used. One embodiment of the present invention is a diethylamine salt of the compound of formula (la), wherein the molar ratio of the compound of formula (a) to diethylamine is 1: 1. Preferably, the diethylamine salt of the compound of formula (la) is crystalline. The diethylamine salt of the compound of formula (la) can be prepared by reaction of the compound of formula (la) with diethylamine; in a mixture of (a) a polar solvent or a mixture thereof, such as methanol, ethanol, and the like, and (b) an anti-solvent or mixtures thereof, such as ethanol, heptane, ethyl acetate , isopropyl acetate, t-butyl methyl ether (MTBE), and the like, for example in a mixture of methanol / ethanol, methanol / isopropyl acetate, methanol / MTBE, and the like; and then separating the salt, for example by precipitation of the solid, preferably through cooling or evaporation of the solvents, at least partially. One embodiment of the diethylamine crystal salt of the compound of formula (la) can be characterized by its X-ray diffraction pattern, as listed in Table A1 below.TABLE A1 X-ray diffraction pattern of the diethylamine salt One embodiment of the present invention is a crystalline diethylamine salt of the compound of formula (la) characterized by major X-ray diffraction peaks having a relative intensity greater than or equal to about of 10%, as listed in Table A1, above. Another embodiment of the present invention is a piperizine salt of the compound of formula (la), wherein the molar ratio of the compound of formula (Ia) to piperizine is 2: 1. Preferably, the piperizine salt of the compound of formula (la) is crystalline. The piperizine salt of the compound of formula (la) can be prepared by reacting the compound of formula (la) with piperizine; in a mixture of (a) a polar solvent or a mixture thereof, such as methanol, ethanol, and the like, and (b) an anti-solvent or mixture thereof, such as ethanol, heptane, ethyl acetate , isopropyl acetate, t-butyl methyl ether (MTBE), and the like, for example in a mixture of methanol / ethanol, methanol / isopropyl acetate, methanol / MTBE, and the like; and then the separation of the salt, as for example by precipitation of the solid, preferably through cooling or evaporation of the solvents, at least partially. An embodiment of the crystalline piperizine salt of the compound of formula (la) can be characterized by its ray diffraction pattern X, as listed in Table A2 below.

TABLE A2 X-ray diffraction pattern of the piperazine salt One embodiment of the present invention is a crystalline piperizine salt of the compound of formula (la) characterized by the major X-ray diffraction peaks having a relative intensity greater than or equal to about 10%, as listed in Table A2 , previous.

Another embodiment of the present invention is a 1- (2-hydroxyethyl) pyrrolidine salt of the compound of formula (la), wherein the molar ratio of the compound of formula (Ia) to 1- (2-hydroxyethyl) pyrrolidine is 1: 1. .

Preferably, the 1- (2-hydroxyethyl) pyrrolidine salt of the compound of formula (la) is crystalline. The 1- (2-hydroxyethyl) pyrrolidine salt of the compound of formula (la) can be prepared by reacting the compound of formula (la) with 1- (2-hydroxyethyl) pyrrolidine; in a mixture of (a) a polar solvent or a mixture thereof, such as methanol, ethanol, and the like, and (b) an anti-solvent or mixture thereof, such as ethanol, heptane, ethyl acetate , isopropyl acetate, t-butyl methyl ether (MTBE), and the like, for example in a mixture of methanol / ethanol, methanol / isopropyl acetate, methanol / MTBE, and the like; and then separating the salt, for example by precipitation of the solid, preferably by cooling or evaporation of the solvents, at least partially. An embodiment of the crystalline 1- (2-hydroxyethyl) pyrrolidine salt of the compound of formula (la) can be characterized by its X-ray diffraction pattern, as listed in Table A3, below.

TABLE A3 X-ray diffraction pattern of salt 1- (2-hydroxyethyl) pyrrolidine One embodiment of the present invention is a crystalline 1- (2-hydroxyethyl) pyrrolidine salt of the compound of formula (la) characterized by the major X-ray diffraction peaks having a relative intensity greater than or equal to about 10%, as it is listed in the previous A3 table. The following examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the following claims.

EXAMPLE 1 4- (4-Ethoxy-4-oxobutip-2,3,4,5-tetrahydro-1-rf4-methylphenyl) sulfonin-5-oxo-1H-1-benzazepin-4-carboxylic acid ethyl ester To a suspension of ethyl 2,3,4,5-tetrahydro-1 - [(4-methylphenyl) sulfonyl] -5-oxo-1 H-1-benzazepine-4-carboxylate (3.41 moles, 1323 g) and Ethyl bromobutyrate (3.41 moles, 667 g) in DMF (4787 g) at room temperature is added K2C03 (6.87 moles), 950 g) in one portion. The resulting suspension is stirred at room temperature for 24 hours. HPLC analysis of the reaction mixture shows that the reaction is over. The reaction solution is diluted with EtOAc (11391 g), quenched with 32-34% aqueous HCl solution (1680 g), and further diluted with H20 (9259 g). After separation of the layers, the organic layer is washed with H20 (9259 g), saturated NaHCO3 solution (5054 g), brine (5054 g), and dried over Na2SO4 (1686 g). After filtration and concentration, the yellow oil is crystallized from EtOH (6178 g). The product is isolated as a white solid. p.f. 86-88.5 ° C 1 H NMR (CDCl 3, 300 MHz) d 7.55 (d, J = 8.3 Hz, 2 H), 7.35 (m, 4 H), 7.26 (d, J = 8.3 Hz, 2 H), 4.11 (m, 4 H ), 3.96 (m, 2H), 2.44 (m, 1H), 2.42 (s, 3H), 2.60 (td, J = 7.0, 1.4 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 1H) , 1.49 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H) MS (ESI): m / z 501.9 (MH +) Elemental analysis for C2ßH3? N07S: Calculated: C, 62.26; H, 6.23; N, 2.79; S, 6.39 Found C, 62.15; H, 6.27; N, 2.75; S, 6.44.

EXAMPLE 2 4- (4-Ethoxy-4-oxobutyl) -2,3 A5-tetrahydro-1-r (4-methylphenyl) sulfonin-1 H-1-benzazepin-4-carboxylic acid ethyl ester To a 121-necked three-necked round bottom flask equipped with a mechanical stirrer, a condenser, a thermocouple and an N2-inlet is added 4- (4-ethoxy-4-oxobutyl) -2,3,4,5- Tetrahydro-1 - [(4-methylphenyl) sulfonyl] -5-oxo-1 H-1-benzazepin-4-carboxylic acid ethyl ester (0.60 mol, 300.15 g) and 1.5 liters of dichloroethane. The solution is cooled in an ice-water bath at 3-5 ° C. To the stirred solution is added Et3SiH (2.25 moles, 360 ml) in one portion, followed by the addition of TFA (1.11 moles, 85.9 ml), BF3 * Et 0 (0.72 moles, 91.2 ml) and MeSO3H (3.16 moles, 25.5 ml). The resulting pale yellow solution is stirred and the internal reaction temperature rises from 5 ° C to 30 ° C in 10 minutes. The reaction temperature then slowly decreases to 6-8 ° C after 30 minutes of stirring. The water-ice bath is removed and the reaction solution is stirred at room temperature for 2 hours. TLC analysis of the reaction mixture indicates that the reaction is over. The reaction mixture is diluted with H20 (750 ml) and stirred for 15 minutes. The aqueous layer is separated and the organic layer is washed with H20 (600 ml), a saturated solution of NaHCO3 (600 ml), and brine (1000 ml). The organic solution is dried with MgSO.sub.0. After filtration and concentration, the solvent is removed in vacuo to yield the crude product (276.4 g) as a colorless oil. The crude product is used for the next step without any further purification. H NMR (CDCl 3, 300 MHz) d 7.61 (d, J = 8.3 Hz, 2 H), 7.25 (m, 3 H), 7.12 (m, 3 H), 4.10 (q, J = 7.1 Hz, 2 H), 3.97 (br m, 3H), 3.53 (br m, 1 H), 2.52 (m, 2H), 2.42 (s, 3H), 2.21 (br m, 3H), 1.70 (br m, 1 H), 1.50 (br m, 2H), 1.43 (br m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H) MS (ESI): m / z 488.4 (MH +) Elemental analysis for C26H33N06S : Calculated: C, 64.04; H, 6.82; N, 2.87; S, 6.58 Found: C, 64.28; H, 6.76; N, 2.68; S, 6.46.

EXAMPLE 3 1, 2,3,5-tetrahydro-1-r (4-methylphenyl) sulfonip-2'-oxo-spiro.4H-1-benzazepin-4,1'-cyclopentano1-3'-carboxylate ethyl A solution of 4- (4-ethoxy-4-oxobutyl) -2.3.4 is added to a 3-necked round bottom flask of 51 equipped with a mechanical stirrer, condenser, thermocouple, and N2 inlet. , Ethyl 5-tetrahydro-1 [(4-methylphenyl) sulfonyl)] - 1 H-1-benzazepin-4-caboxylate (1.03 mol, 505.3 g) in toluene (2.5 L). To the stirred solution is added KOt-Bu (1.55 moles, 174.4 g) in two equal portions 30 minutes apart. The temperature of the reaction increases from room temperature to 36 ° C in about 20 minutes and the reaction solution becomes an amber color from a colorless solution. The reaction solution is stirred at room temperature for 20 hours. The reaction mixture is cooled in an ice-water bath at 10-15 ° C, acidified with 2N HCl solution (11), and stirred for 15 minutes. After separation of the layers, the organic layer is washed twice with H20 (1 l), brine (1 l), and dried over MgSO4. After filtration and concentration, the solvent is removed under vacuum at 60 ° C. The crude product is obtained as a pale yellow oil. The crude product is used for the next step without any further purification. 1 H NMR (CDCl 3, 300 MHz) d7.58 (d, J = 8.2 Hz, 2 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.24 (m, 4 H), 7.01 (m, 1 H), 4.22 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.27 (m, 2H), 2.41 (s, 3H), 2.34 (m, 1 H), 2.13 (m, 4H), 1.63 (m , 1 H), 1.52 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H) MS (ESI): m / z 442.0 (MH +). Elemental analysis for C24H2 N05S: Calculated: C, 65.28; H, 6.16; N, 3.17; S, 7.26 Found: C, 65.25; H, 6.29; N, 3.20; S, 7.37. In a repeat of the previous experiment, the crude product is also crystallized from methanol to produce a white solid (p.p. 114-116 ° C).

EXAMPLE 4 1, 2,3,4-tetrahydro-2'-hydroxy-1-r (4-methylphenylsulfonip-spiror4H-1. Benzazepin-4,1'-cyclopentanl-3'-carboxylate ethyl A solution of 1,2,3,5-tetrahydro-1 - [(4-methylphenyl) is added to a 3-neck round bottom flask of 121 equipped with a mechanical stirrer, a condenser, a thermocouple, and an N 2 inlet. ) sulfonyl] -2'-oxo-spiro [4H-1-benzazepin-4,1'-cyclopentan] -3'-carboxylic acid ethyl ester (0.92 mol, 404. 7 g) in methanol (6 1). The solution is cooled to 5-7 ° C in an ice-water bath while stirring and NaBH (0.63 mol, 23.95 g) is added in two equal portions with a 30-minute separation. The temperature of the reaction solution increases to 12-14 ° C after each addition. The reaction solution is stirred in an ice water bath for 30 minutes after the addition. TLC analysis of the reaction solution indicates that the reaction is over. A solution of 1.5 N HCl (1.5 I) is slowly added over 15 minutes to quench the reaction. The warm solution is stirred in an ice-water bath for 15 minutes and at room temperature for 1 hour. 80% methanol is removed in vacuo. The residue is diluted with EtOAc (4 I) and H20 (2 I). After stirring for 15 minutes, the layers are separated.

The aqueous layer is extracted with EtOAc (2 1). The combined organic layer is washed with H20 (2 I), a saturated solution of NaHCO3 (2 I), H20 (2 I), brine (2 I), and dried with MgSO4. After filtration and concentration, the crude product is obtained as a white semi-solid. The crude product is used for the next step without any further purification. The product can be crystallized from EtOAc / hexane (1/3) to provide a white solid (mp 139-140 ° C) if necessary. 1 H NMR (CDCl 3, 300 MHz) d7.56 (d, J = 8.2 Hz, 2H), 7.35 (m, 1H), 7. 22 (m, 3H), 7.17 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.87 (br m, 1 H), 3.71 (m, 1 H), 3.57 (br m, 1 H ), 3.02 (br s, 1 H), 2.91 (m, 1 H), 2.43 (br s, 1 H), 2.41 (s, 3H), 2.27 (m, 1 H), 205 (m, 1 H), 1.88 (m, 1 H), 1.57 (m, 2H), 1.45 (m, 1 H), 1.26 (m, 1 H), 1.24 (t, J = 7.1 Hz, 3H) MS (ESI): m / z 443.9 (MH +) Elemental analysis for C24H29N05S: Calculated: C, 64.99; H, 6.59; N, 3.16; S, 7.23 Found: C, 64.96; H, 6.69; N, 3.06; S, 7.06. In a repeat of the above experiment, the crude product is also crystallized from EtOAc / hexane (1/3) to give a white solid (mp 139-140 ° C).

EXAMPLE 5 1, 2,3,5-Tetrahydro-spiror-4H-1-benzazepin-4,1'-12. Cyclopentanl-3'-carboxylic acid A solution of 1, 2,3,5-tetrahydro-2'-hydroxy is added to a 12-necked 3-necked round bottom flask equipped with a mechanical stirrer, a condenser, a thermocouple, and an N 2 inlet. -1-I- (4-methylphenyl) suIfoniI] -spiro [4H-1-benzazepin-4,1'-cyclopentan] -3'-carboxylic acid ethyl ester (1.1 moles, 487.9 g) in acetic acid (950 ml). To the solution is added H2SO4 (475 ml) concentrated in one portion. The pale yellow solution turns a dark brown color and the temperature of the reaction mixture increases to 80 ° C. The reaction is warmed to 100 ° C and stirred for 22-24 hours. The dark brown solution is cooled to room temperature and diluted with cold H2O (1 I). The solution is then cooled to 10 ° C in an ice-water bath and neutralized to a pH of 5.5 by the slow addition of a 7M KOH solution (4.4 I) for 1 hour. The temperature of the solution is kept below 50 ° C. The mixture is then diluted with 20% THF in EtOAc (1.8 L) and stirred for 30 minutes. The mixture is then filtered through a celite filter pad and the filter cake is rinsed with 20% THF in EtOAc (1.8 L). After separation of the filtrate layers, the aqueous layer is extracted with 20% THF in EtOAc (1.8 L). The combined organic layer is stirred with MgSO4 (200 g) and Dacco G-60 charcoal (120 g) for 1 hour. After filtration, the filtrate is concentrated in vacuo to yield brown oil. The crude oil is dissolved in EtOAc (540 ml) and stirred at room temperature for 20 hours. The beige solids are crystallized from the solution. The mixture is further diluted with heptane (700 ml) and stirred for an additional 5 hours at room temperature. The solid product is collected by vacuum filtration, rinsed with a mixture of EtOAc and heptane (1: 4) (700 ml), and dried in a vacuum oven at 45 ° C for 24 hours. The product is obtained as a beige colored solid. p.f. 162-164 ° C 1 H NMR (CDCl 3, 300 MHz) d 7.86 (br s, 2 H), 7.04 (m, 2 H), 6.76 (s, 1 H), 6.73 (m, 2H), 3.16 (m, 1H), 3.05 (m, 1 H), 2.80 (d, J = 41.9, 13.6 Hz, 2H), 2.60 (m, 2H), 1.81 (m, 4H) MS (ESI): m / z 244.1 (MH +) Elemental analysis for C? 5H? N02; Calculated: C, 74.05; H, 7.04; N, 5.76 Found: C, 73.82; H, 7.33; N, 5.95.

EXAMPLE 6 (1R) -7-dimethyl-2-oxo-bicyclo (2R) -7-dimethyl-2-benzazepin-1-methanesulfonic acid acid salt (4R) -1,2,3,5-tetrahydro-1 , 1'-F2.c.clopenten1-3, -carboxylic The 1,2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1'- [2] cyclopentene] -3'-carboxylic acid (7.02 moles, 1708 g) is suspended in 16 liters of methanol and It is heated from 65 to 70 ° C. After 1 hour, a solution of (-) - camphorsulfonic acid (5.61 moles, 13.04 g) in methanol (10 L) is added over 30 minutes. The reaction mixture is heated to reflux for one hour. The mixture is then cooled to room temperature and the product salt of (1S) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptan-1-methanesulfonic acid (4R) -1,3,3 , 5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2-cyclopenten] -3'-carboxylic acid, is isolated by vacuum filtration. The crude product is purified by crystallization from methanol (20 L). The product is isolated as a whitish to beige solid. p.f. 289-291 ° C 1 H NMR (DMSO-de, 300 MHz) d 7.46 (m, 1 H), 7.35 (m, 3 H), 6.38 (s, 1 H), 3.44 (br m, 1 H), 3.30 ( br m, 1 H), 3.10 (m, 2H), 2.92 (m, 2H), 2.62 (m, 2H), 2.51 (m, 2H), 2.47 (m, 2H), 2.26 (m, 1 H), 2.06 (m, 1 H), 1.94 (m, 2H), 1.84 (m, 2H), 1.64 (m, 2H), 1.29 (m, 2H), 1.04 (s, 3H), 0.75 (s, 3H) MS (ESI): m / z 244.1 (MH +) Elemental analysis for C25H 3N06S; Calculated: C, 63.13; H, 6.99; N, 2.95; S, 6.74 Found: C, 62.86; H, 6.91; N, 2.77; S, 6.76.

EXAMPLE 7 Acid (4R) -1-r4-r (H, 1'-biphenyl-l-2-ylcarbonamino-benzoic-1, 2,3,5-tetahydro-spiror-4H-1-benzazepin-4,1'-r21-cyclopentene-1 3'-carboxHico A solution of 4- (2-phenylbenzoyl) aminobenzoic acid (0.105 mole, 33.4 g) in 241 ml of toluene is treated with thionyl chloride (0.21 mole, 25.0 g) and a catalytic amount of DMF (0.009 mole, 0.66 g) at 95 ° C for 1 hour and at 100 ° C for an additional hour. The majority of the toluene is then removed by distillation (180 ml). The resulting suspension is diluted in dichloromethane (185 ml) to yield the acid chloride suspension to be used in the next step. In a separate reaction vessel, an acid solution (1S) -7,7-dimethyl-2-oxo-bicyclo- [2.2.1] heptane-1-methanesulfonic acid (4R) -1,2,5,5-tetrahydro-spiro [4H-1-benzazepin- 4,1 '- [2] cyclopentene] -3'-carboxylic acid (0.105 mol, 50.0 g) and pyridine (0.63 mol, 49.9 g) in toluene (172 ml) is treated with chlorotrimethylsilane (0.346 mol, 37.7 g) at 0 ° C for one hour. At this temperature the suspension of the acid chloride which was prepared as described above is added to the reaction mixture. After stirring for 20 hours, the reaction mixture is quenched by the addition of aqueous hydrochloric acid (16%, 0.4 moles, 83.0 g). Most of the dichloromethane (127 ml) is then removed by distillation at 85 ° C and the residue is dissolved again in DMF (235 ml) at 100 ° C. At this temperature the water (110 ml) is added and the reaction mixture is cooled to room temperature. The product is precipitated and collected by vacuum filtration. The filter cake is washed with a mixture of ethanol / water (1: 1, 86 ml), water (172 ml), and dried in a vacuum oven at 75 ° C for 24 hours. The product is isolated as a whitish solid, m.p. 263-265 ° C 1 H NMR (DMSO-d 6, 300 MHz) d 12.3 (s, 1 H), 10.3 (s, 1 H), 7.54 (m, 2H), 7.44 (m, 2H), 7.33 (m, 7H), 7.06 (m, 4H), 6.66 (br m, 1.6H), 6.23 (br s, 0.4H), 4.76 (br m, 1 H), 3.34 (m, 1 H), 2.81 (m, 1 H), 2.50 (m, 4H), 1.91 (m, 2H), 1.58 (m, 2H). MS (ESI): m / z 543.4 (MH +).

EXAMPLE 8 Benzoate of (4R) -1-? 4-U .1, 1'-biphenip-2-ylcarbonyl) amino-1-benzoyl-N-f2- (dimethylamino) ethyl 1-1.2.3.5-tetahydro-spiro .4H-1-benzazepin-4.1'-r21cyclopenten-3'-carboxamide A solution of (4R) -1- [4 - [([1,1'-biphenyl] -2-alkylcarbonyl) amino] benzoyl] -1,2,3,5-tetahydro-spyr [4H-] 1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid (0.085 mol, 46.12 g) in toluene (460 ml), treated with thionyl chloride (0.116 mol, 13.81 g). The reaction mixture is heated to 100 ° C and stirred for 2 hours. The reaction mixture turns to a clear solution. The toluene and the excess amount of thionyl chloride are then distilled. The resulting crude acid chloride was dissolved in a mixture of dichloromethane and EtOAc (ratio 1/3, 400 g) and added to a solution of N, / V-dimethylaminoethylamine (0.105 moles, 9.70 g) and triethylamine ( 0.092 moles, 9.31 g) in EtOAc (400.0 g) at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 1 hour and then quenched with aqueous hydrochloric acid (10%, 150.0 g). After separation of the layers, the aqueous layer was treated with aqueous sodium hydroxide (27%, 137.0 g) until the pH of the mixture became approximately 10. The aqueous layer was extracted with EtOAc (500.0 g) and dried with sodium sulfate. Approximately half of the solvent was distilled off to yield a solution of the title product as a free base. To the solution of the free base at 50 ° C was added a solution of benzoic acid (0.17 mol, 20.71 g) in EtOAc (300.0 g). The product was precipitated after stirring at 60 ° C for 1 hour and 20 ° C for 4 hours. The precipitate was then collected by vacuum filtration, and dried in a vacuum oven at 60 ° C for 16 hours. The product . it was isolated as a white solid. P.f. 180-185 ° C (decomp.) 1 H NMR (DMSO-d 6, 300 MHz) d 10.30 (s, 1 H) 9, 7.94 (d, J = 7.0 Hz, 2H), 7.80 (m, 1 H), 7.57 (m, 3H), 7.47 (m, 4H), 7.33 (m, 8H), 7.11 (m, 4H), 6. 67 (br t, = 8.0 Hz, 1 H), 6.44 (br s, 0.6 H), 6.10 (br s, 0.4 H), 4.68 (br m, 1 H), 3.26 (m, 3 H), 2.82 (m , 1 H), 2.50 (s, 2H), 2.46 (m, 4H), 2.26 (s, 3.6H), 2.19 (s, 2. 4H), 1.89 (m, 2H), 1.54 (m, 2H) MS (ESI): m / z 613.0 (MH +) Elemental analysis for C46H 6N 05: Calculated: C, 75.18; H, 6.31; N, 7.62 Found: C, 74.92; H, 6.19; N, 7.43 EXAMPLE 9 4-r (biphenyl-2-carbonyl) -amino-1-benzoyl chloride A mixture of 2-biphenylcarboxylic acid (25 g, 0.13 mol) in thionyl chloride (80 ml) was stirred at room temperature overnight and the excess SOCI2 was removed under reduced pressure to produce biphenyl-2-carbonyl chloride as a yellow oil The oil was dissolved in methylene chloride (60 ml) and added slowly through an addition funnel to a solution of methyl-4-aminobenzoate (20 g, 0.13 mol) and triethylamine (28 ml, 0.198 mol) was dissolved in methylene chloride (400 ml). The resulting mixture was stirred at room temperature for 4-5 hours and water (500 ml) was added. The layers separated; the CH2Cl2 layer was dried over MgSO4 and the solvent was removed under reduced pressure. The resulting solids were washed with diethyl ether and dried to produce methyI-4 - [(biphenyl-2-carbonyl) -aminoj-benzoate as a tan solid. P.f. 160-161 ° C To a stirred solution of methyl-4 - [(biphenyl-2-carbonyl) -amino] -benzoate (37 g, 0.11 M) in CH 3 OH (400 mL) was slowly added 6.6N NaOH (100 mL). Stirring continued until all solids dissolved (approximately 6 hours). The methanol was removed under reduced pressure, solids were dissolved in H20 and concentrated HCl was slowly added to the stirred solution. The mixture was stirred at room temperature overnight and the precipitates of the resulting white solid were collected and dried to yield 4 - [(biphenyl-2-carbonyl) -amino] -benzoic acid as a white crystalline solid. MS: m / z (M +) 318 4 - [(Biphenyl-2-carbonyl) -amino] -benzoic acid (34 g, 0.1 M) was stirred in thionyl chloride (260 ml) with gentle heating (40 ° C) , oil bath) for 4 hours. The residual semi-solid was diluted with toluene and filtered to yield the title product as a white solid. P.f. 148-150 ° C.

EXAMPLE 10 Phosphate of (1?) - / V-.2- (dimethylamino?) Etip-1-.4 -. (2-fluorobenzoi-amino-benzoic-1,2,3,5-tetrahydrospyror-4H-1-benzazepin-4,1, -. 21-cyclopentenyl-3'-carboxamide Step A: 4-Aminobenzoic acid (20.0 g, 0.146 moles) was suspended in toluene at room temperature. Pyridine (50.76 g, 0.646 moles) was added and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled to 0 ° C and chlorotrimethylsilane (98.0 g, 2.2 moles) was added. The reaction mixture was stirred at 0 ° C for 30 minutes. A solution of 2-fluorobenzoyl chloride (23.14 g, 0.146 moles) in toluene was then added for 15 minutes. The resulting mixture was added at 0 ° C for 1.5 hours. The reaction was quenched with aqueous hydrochloric acid and diluted with ethanol (100 mL). After stirring at room temperature for 15 minutes, the mixture was heated at 85 ° C for 30 minutes. The reaction mixture was then cooled to room temperature, resulting in the precipitation of a white solid. The solid product was isolated by vacuum filtration, washed with water and ethanol, and dried in a vacuum oven to yield 4- (2-fluoro-benzoylamino) -benzoic acid as a white solid.

The solid 4- (2-fluoro-benzoylamino) -benzoic acid prepared as mentioned above (127.22 g, 0.105 mol) was suspended in toluene (650 ml) at room temperature. Thionyl chloride (1.5 molar equivalents) and a catalytic amount of DMF were added and the mixture was heated at 100 ° C for 1 hour until the suspension became a clear solution. The reaction solution was concentrated in vacuo to yield 4- (2-fluoro-benzoylamino) -benzoyl chloride, which was diluted in dichloromethane (350 ml) for the next step.

Step B: In a separate reaction vessel, the salt of (1 R) - (-) - camphorsulfonic acid of 1,2,3,5-tetrahydro-spyrro [4H-1-benzazepine-4,1'- [2] cyclopenten] -3'-carboxylic acid (50.0 g, 0.105 mol) was suspended in toluene (450 mL) at room temperature. Pyridine (6.0 molar equivalents) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was then cooled to 0 ° C and chlorotrimethylsilane (3.3 molar equivalent) was added. The mixture was stirred at 0 ° C for 30 minutes. The 4- (2-fluoro-benzoylamino) -benzoyl chloride prepared as mentioned above (1.0 molar equivalent) was added for 15 minutes. The resulting mixture was stirred at 0 ° C for 2 hours and then quenched with aqueous hydrochloric acid (32-34% 40.0 g, 0.42 moles). The solvents were distilled off at 65 ° C. During the distillation, the product was precipitated as a white solid. After cooling to room temperature, the resulting solid product, (4R) -1- [4 - [(2-fluorobenzoyl) amino] benzoyl] -1, 2,3,4-tetrahydro-spiro [4H-1-benzazepin] -4, - [2] cyclopenten-3'-carboxylic acid was isolated by vacuum filtration, washed with water, recrystallized from ethanol / H20.

Step C: The solid product prepared as in step B above (40.0 g, 0.082 mol) was suspended in toluene (350 mL) at room temperature. Thionyl chloride (2.0 molar equivalents) and a catalytic amount of DMF were added and the mixture was heated at 100 ° C for one hour until the suspension became a clear solution. The solvent was then removed in vacuo to yield the corresponding acid chloride product, which was diluted in EtOAc (400 mL) and used in the subsequent steps without further purification.

Step D: In a separate reaction vessel, N, N'-dimethylethylenediamine (8.72 g, 0.098 mol) was dissolved in EtOAc (250 mL) at room temperature. Triethylamine (1.3 molar equivalent) was added and the mixture was cooled to 0 ° C and stirred for 30 minutes. The acid chloride solution prepared as in step C above (1.0 molar equivalent) in EtOAc was added for 15 minutes. The resulting mixture was stirred at 0 ° C for 1.5 hours and then quenched with aqueous hydrochloric acid. The layers were separated and the organic layer was extracted once with aqueous hydrochloric acid (32-34%8.98 g, 0.246 moles). The combined aqueous layer was treated with aqueous sodium hydroxide solution until the pH value of the mixture became greater than 10. The aqueous layer was extracted twice with EtOAc (200 mL): The combined organic layer was dried over sulfate of sodium (50.0 g). After filtration and concentration, the corresponding crude product, (4R) -1- [4 - [(2-fluorobenzoyl) amino] benzoyl] -N- [2- (dimethylamino) ethyl] -1, 2.3, 4-tetrahydro-spiro ^ Hl-benzazepin ^ .l'-PJcyclopentenj-S'-carboxamide, was obtained as a white off-white solid.

Step E: The crude amine product prepared as in step D above (8.12 g, 0.016 mole) was dissolved in methanol (100 mL) and heated to 70 ° C. Water was added (-1.5 molar equivalents.). A solution of phosphoric acid (0.9 molar equivalent, based on the raw product test) in methanol was added at 70 ° C for 30 minutes, followed by the addition of methyl tert-butyl ether (200 mL) until the solution was It turned cloudy. The mixture was cooled to room temperature and the title compound salt, (4R) -1- [4 - [(2-fluorobenzoyl) amino] benzoyl] -N- [2- (dimethylmethane) phosphate. ) ethyl] -1,2,3,4-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxamide was precipitated slowly and isolated by vacuum filtration after 16 hours. hours to a light beige solid. P.f. 148-158 ° C (decomp.) 1 H NMR (DMSO-d 6) 300 MHz) d 10,50 (s, 1 H), 8.1 (br, m, 1 H), 7.56 (m, 4 H), 7.33 (m, 3H), 7.12 (m, 5H), 6.69 (m, 1 H), 6.54 (s, 0.6H), 6.14 (s, 0.4H), 4.73 (m, 1 H), 3.35 (m, 3H), 2.80 (m, 3H), 2.59 (m, 3H), 2.52 (s, 3.6H), 2.45 (m, 2.4H), 1.91 (m, 2H), 1.55 (m, 2H) MS (ESI): m / z 555.4 (MH +) Elemental analysis for C33H35FN4? 3 H3P04: Calculated: C, 60.73; H, 5.87; F, 2.91; N, 8.58; P, 4.75 Found: C 59.82; H, 6.13; F, 2.94; N, 8.54; P, 4.57.

EXAMPLE 11 3-Methoxy-4-nitro-benzoic acid methyl ester A 3-neck, 3-necked round bottom flask fitted with an overhead stirrer and a 250 mL addition funnel was charged with 3-hydroxy-4-nitrobenzoic acid (122 g, 0.66 mol), acetone (reagent grade 1.5 L) and K2C? 3 powder (185 g). To this stirred suspension was added dimethisulfate (127 mL) dropwise. The suspension was stirred at room temperature for 18 hours and filtered. The filtrate was concentrated under reduced pressure about half the volume (ca 750 mL), transferred to a 3 L beaker and water (1-L) was added with stirring. The precipitated product was collected by filtration and dried under vacuum to obtain the title compound as a white crystalline solid. P.f. 87-88 ° C MS (M + H) + = 212.1 1 H NMR (400 MHz, CDCl 3) d: 7.77 (d, J = 8.3, 1 H), 7.68 (d, J = 1.5 Hz, 1 H), 7.63 (d, J = 8.3 Hz, 1 H), 3.94 (s, 3 H), 3.90 (s, 3H).

EXAMPLE 12 4-Amino-3-methoxy-benzoic acid methyl ester To a Parr 2 L high pressure hydrogenation bottle, (glass classified in 5.62 Kg / cm2) was charged Pd / C (10% by weight in carbon, 5 g), EtOAc (800 mL) and methyl ester of 3-methoxy-4-nitrobenzoic acid (120.5 g, 0.57 mol) . The reaction mixture was charged with H2 (2.10 Kg / cm2) in a Parr apparatus. The loading of H2 was continued carefully several times until the pressure remained stable. This took approximately 3 hours. The reaction was stirred for an additional 0.5 hours. After hydrogenation, the reaction mixture was diluted with ethyl acetate to dissolve some of the precipitated product and passed directly through a small pad of Celite and washed with EtOAc. The solvent was evaporated to yield 4-amino-3-methoxy-benzoic acid methyl ester as a white solid. MS (electro spray, positive mode), (M + H) + 182.1 1 H NMR (400 MHz, CDCl 3) d: 7.55 (d, J = 8.1, 1.7 Hz, 1 H), 7.45 (d, J = 1.7 Hz, 1 H), 6.66 (d, J = 8.1 Hz, 1 H), 4.21 (s, 2 H), 3.90 (s, 3 H) 3.86 (s, 3 H).

EXAMPLE 13 4- (2-Chloro-5-fluoro-benzoylamino) -3-methoxy-benzoic acid methyl ester A dry, 3 L, 3-neck round bottom flask equipped with a thermometer and addition funnel was charged with a solution of 4-amino-3-methoxy-benzoic acid methyl ester (96 g, 0.53 moles, 1.0 equiv.) and Et3N (88 ml, 0.64 moles, 1.2 equiv.) in CH2Cl2 (1.2 L). The solution was cooled to 0 ° C by a bath with ice and 2-chloro-5-fluoro-benzoyl chloride (110 g, 0.57 mol, 1.05 equiv.) Was added dropwise during 40 minutes at 0 ° C. After the addition, the reaction mixture was stirred at 0 ° C for an additional 1.5 hours. The organic layer was washed with brine three times, dried over MgSO4, filtered and evaporated to yield 4- (2-chloro-5-fluoro-benzoylamino) -3-methoxy-benzoic acid methyl ester as a white solid.

MS (electro spray, positive mode), (M + H) + 338.0 1 H NMR (400 MHz, CDCl 3) d: 8.84 (s, 1 H), 8.61 (d, J = 8.4 Hz, 1 H), 7.75 (dd , J = 8.4, 1.7 Hz, 1 H), 7.60 (d, J = 1.7 Hz, 1 H) 7.55 (dd, J = 8.4, 3.0 Hz, 1 H) 7.45 (dd, J = 8.4, 4.8 Hz, 1 H) 7.20-7.13 (m, 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H).

EXAMPLE 14 4- (2-Chloro-5-fluoro-benzoylamino) -3-methoxy-benzoic acid LiOH (14.1 g, 0.59 mol, 1.1 equiv.) Dissolved in H20 (200 mL) was added dropwise over 45 minutes to a solution of 4- (2-chloro-5-fluoro-benzoylamino) -3-methyl ester. -methoxy-benzoic acid (180 g, 0.53 mol, 1 equiv.) in THF (1800 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue redissolved in water (ca 3 L). The insoluble solid was separated by filtration. Under vigorous stirring, the aqueous filtrate solution was acidified with concentrated aqueous HCl solution (37%) to achieve pH < 2. The precipitate of the resulting white solid was filtered and washed with water. The wet filter cake was then transferred to a flask and dried on a rotary evaporator under vacuum at 50 ° C overnight to produce 4- (2-chloro-5-fluoro-benzoylamino) -3-methoxy-benzoic acid as a dry fine white powder. MS (electro spray, negative mode), (MH) "322.0.1H NMR (400 MHz, DMSO-d6) d: 12.90 (s, 1 H), 10.01 (s, 1 H), 8.22 (d, J = 8.3 Hz, 1 H), 7.65-7.45 (m, 4 H), 7.45-7.30 (m, 1 H), 3.88 (s, 1 H).

EXAMPLE 15 4- (2-Chloro-5-fluoro-benzoylamino) -3-methoxy-benzoyl chloride The 4- (2-chloro-5-fluoro-benzoylamino) -3-methoxy-benzoic acid (152 g, 0.45 mol, 1 equiv.) In CH2Cl2 (1.5 L) was suspended and DMF (1 mL) was added. Oxalyl chloride (71.6 g, 0.56 mol, 1.2 equiv.) Was added dropwise during 30 minutes at 0 ° C. After the addition, the cold bath was removed and the reaction mixture was further stirred at room temperature for 3.5 hours. The solvent and any unreacted oxalyl chloride were evaporated to yield a white solid, which was further dried on a rotary evaporator under vacuum at 40 ° C overnight to produce 4- (2-chloro-5-fluoro-benzoylamino chloride. ) -3-methoxy-benzoyl dry as a white solid.

The title compound was isolated substantially free of side products having the ortho and / or para positions to the halogenated methoxy group. The terms "substantially free of by-products" in this context mean that said by-products are not detected by HPLC. MS (electro spray, negative mode), (MH) "339.9 1 H NMR (400 MHz, CDCl 3) d: 8.97 (s, 1 H), 8.71 (d, J = 8.6 Hz, 1 H), 7.91 (dd, = 8.6, 1.9 Hz, 1 H), 7.60 (d, J = 1.9 Hz, 1 H) 7.57 (dd, J = 8.6, 3.1 Hz, 1 H) 7.47 (dd, J = 8.6, 4.8 Hz, 1 H) 7.21 -7.15 (m, 1 H), 3.99 (s, 3 H).

EXAMPLE 16 (4?) - 1, 2,3,5-Tetrahydro-spiro.4H-1-benzazepin-4,1'-r21-cyclopentene-3'-carboxylic acid In a 5-L, 3-neck round bottom flask fitted with an air pump stirrer, (4R) -2,3,4,5-tetrahydrobenzazepin-4-spiro-3'-cyclopentyl was suspended. 1'-en-carboxylic acid (1 R, 4 S) -7,7, -dimethyl-2-oxo-bicyclo [2.2.1] heptane-methanesulfonate (500 g, 1.05 mol) in H 2 O (2 L) for producing a reaction mixture with a pH of about 3-4. With an addition funnel, the saturated aqueous NaHC 3 solution was slowly added to the mixture to a pH of 6. CH 2 Cl 2 (1 I) was then added and the suspension mixture was stirred for 1 hour. Any remaining starting material in the mixture was then separated by filtration. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 150 mL). The combined organic layer was dried with Na 2 SO 4, filtered and concentrated to yield (4R) -1,2,3,5-tetrahydro-spyrro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid as a dark gray solid.

To the remaining starting material, the procedure was repeated again until all the salts were completely converted to free acid. All the acid (4f?) - 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1, - [2] cyclopenten] -3'-carboxylic acid was combined, suspended in EtOAc / hexanes (1: 1). stirred overnight at room temperature and subsequently filtered to yield (4R) -1,2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'- carboxylic acid as a gray solid in a yield of 88%. MS (electro spray, positive mode), (M + H) + 244.1.0. 1 H NMR (400 MHz, CDCl 3) d 7.09-7.01 (m, 2 H), 6.76 (t, J = 6.3 Hz, 1 H), 6.77 (s, 1 H), 6.72 (d, J = 7.6 Hz, 1 H ), 3.17-3.14 (m, 1 H), 3.07-3.05 (m, 1 H), 2.82 (dd, J = 53.3, 13.64 Hz, 2H), 2.71-2.54 (m, 2H), 1.92-1.68 (m , 4H).

EXAMPLE 17 (4R) -1,2,3,5-Tetrahydro-Spiror4H-1-Benzazepin-4,1'-r2. Cyclopentene-3'-carboxylic acid ethyl ester In a 3-L, 3-neck round bottom flask fitted with an inlet thermometer and air pump stirrer, (4R) -1, 2,3,5-tetrahydro-spiro [4H] was suspended in suspension. -1-benzazepin-4,1'- [2] cyclopenten] -3'-carboxylic acid (225.0 g ,.92 mol) in EtOH (1 L). The flask was then cooled in an ice bath and slowly concentrated H2SO (90 g) was added while maintaining the internal temperature between 15 and 25 ° C. The ice bath was removed after the addition was complete and the reaction was stirred overnight at room temperature. The reaction was 98% complete after the reaction mixture was heated for another 5 days at 40 ° C. The reaction mixture was concentrated to a black oil, diluted in CH 2 Cl 2 (1 L), then washed with H 2 O (2 X 500 mL), saturated NaHCO 3 solution (1 x 1 L) and saturated NaCl solution (1 x 1 L). The extracted organic layer was dried with Na 2 SO, filtered and concentrated to yield (4R) -1, 2,3,5-tetrahydro-spiro [4 H-1-benzazepin-4,1 '- [2] cyclopenten ethyl ester. ] -3'-carboxylic acid as a black oil. The ethyl ester of (4f?) - 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid was purified by means of chromatography by filtration (column of silica gel 14 cm OD, 8 cm in height and eluted with 4/1 hexanes / EtOAc). The desired fractions were combined to recover the (4R) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid ethyl ester as a dark red oil. The chromatography by filtration was repeated again and the fractions containing the product were combined to produce the ethyl ester of (4R) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1] '- [2] cyclopenten] -3'-carboxylic acid as a yellow oil. MS (electro spray, positive mode), (M + H) + 272.1. 1 H NMR (400 MHz, CDCl 3) d 7.08-7.01 (m, 2H), 6.83 (t, J = 7.3 Hz, 1 H), 6.71 (d, J = 7.8 Hz, 1 H), 6.63 (t, J = 2.0 Hz, 1 H), 4.18 (dd, J = 14.4, 7. 3 Hz, 2H), 3.77 (br s, 1 H), 3.19-3.13 (m, 1 H), 3.01-3.0 (m, 1 H), 2.81 (dd, J = 56. 6, 13.6 Hz, 2H), 2.70-2.53 (m, 2H), 1.91-1.65 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H).

EXAMPLE 18 Ethyl ester of (4R) -1-r4- (2-Chloro-5-fluorobenzoi-3-mexoxybenzoic-1, 2,3,5-tetrahydro} 4 H-1-benzazepin-4,1 '-icyclopentenyl-S'-carboxylic acid In a 3 L round bottom flask, a dry neck fitted as an air pump stirrer, ethyl ester of (4R) -1, 2,3,5-tetrahydro- was combined. { 4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid (105 g, 0.39 mol) and (4- (2-chloro-5-fluoro-benzoyl) amino-3-methoxy chloride -benzoyl (146 g, 0.43 mol) in CH 2 Cl 2 (1 L) The reaction mixture (suspension) was cooled using an ice bath at 0 ° C and triethylamine (65 mL, 0.47 mol, 1.2 eq) was slowly added during a period of 15 minutes The ice bath was removed and the reaction mixture allowed to warm to room temperature After 30 minutes the HPLC analysis indicated that the reaction was completed The reaction mixture was warmed with H20 (500 mL ) and the layers were separated The organic layer was washed with saturated NaHCO 3 solution (1 x 500 mL) and saturated NaCl solution (1 x 500 mL) The extracted organic layer was dried with Na 2 SO 4 and filtered. crude product was concentrated to oil and purified by filtration chromatography (silica gel column: 14 cm OD, 8 cm in height and eluted with 4/1 EtOAc / hexane s) The desired fractions were combined to produce (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1,3,3-ethyl ester. 5-tetrahydro. { 4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid as an orange oil. MS (electroaspersion, negative mode), (M + H) + 577.0. 1 H NMR (400 MHz, CDCl 3) d 8.66 (s, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 7.48 (dd, J = 8.6, 3.0 1 H), 7.41 (dd, J = 8.6, 4.5 Hz, 1 H), 7.22-7.09 (m, 3H), 7.0 (t, J = 7.0 Hz, 1 H), 6.94 (s, 1 H), 6.75-6.67 (m, 2H), 4.84 (bd, J = 48 Hz, 1 H), 4.25-4.14 (m, 2H), 3.72 (s, 3H), 3.33 (dd, J = 13.4, 4.5 Hz, 1 H), 3.16-2.96 (m, 1 H), 2.75-2.61 (m, 3H), 2.13-1.93 (m, 2H), 1.79-1.72 (m, 3H) ), 1.34-1.22 (m, 3H).

EXAMPLE 19 Acid (4R) -1-f4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoin-1, 2,3,5-tetrahydro-spiror4H-1-benzazepin-4,1, -r21-cyclopenten-3 , -carboxylic A (4?) - 1- [4- (2-chloro-5-fluorobenzoyl) amino acid ethyl ester was diluted in a 2-L round bottom flask fitted with a magnetic stir bar. 3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopentene-3'-carboxylic acid (220.0 g, .38 mol) in EtOH / THF (350 mL / 350 mL). A warm solution (ca. 60-70 ° C) of LiOH (13.7 g, 0.57 mol) in H20 (200 mL) was slowly added dropwise to a solution over a period of 15 minutes. The reaction mixture was stirred and allowed to cool to room temperature overnight. The reaction mixture was concentrated to an oil, treated with H20 (1 L), transferred to a separatory funnel and washed with EtOAc (1x500 mL). The aqueous layer was acidified to pH 1-2 using 3 M HCl, then extracted with EtOAc (2x500 mL). The extracted organic layer was dried with Na 2 SO 4, filtered and concentrated under reduced pressure until the precipitation developed in the flask. The precipitated solids were treated with Et20 / hexanes (600 mL / 200 mL) and stirred for 2 hours and then filtered. The filtered solids were dried in a top vacuum pump overnight in a rotovap (rotary evaporator) at 60 ° C to yield the title compound, (4R) -1- [4- (2-chloro-5-fluorobenzoyl ) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 2] cyclopenten] -3'-carboxylic acid as a white solid. P.f. 178-180 ° C MS (electroaspersion, negative mode), (M + Na) 571.0 1 H NMR (400 MHz, CDCl 3) d 8.66 (s, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 7.48 (dd, J = 8.6, 3.3 Hz, 1 H), 7.41 (dd, J = 8.8, 4.8 Hz, 1 H), 7.23-7.1 (m, 3H), 7.0 (t, J = 7.8 Hz, 1 H) , 6.73-6.67 (m, 2H), 4.86 (bd, J = 49.7 Hz, 1 H), 3.73 (s, 3H), 3. 35 (dd, J = 13.6, 5.0 Hz, 1 H), 3.15-2.96 (m, 1 H), 2.76-2.62 (m, 3H), 2.15-2.0 (m, 2H), 1.82-1.54 (m, 2H) ) EXAMPLE 20 1 -Í4-. (M, 1'-Bifenin-2-ylcarbonyl) amino-1-benzoyl-N2- (dimethylamine) ethyn-1, 2,3,5-tetrahydro-2'-oxospyror4H-1-benzazepin-4,1 ' -cyclopentanl-3'-carboxamide Step A: Ethyl 4- (3-ethoxycarbonyl-propyl) 5-oxo-1- (toluene-4-sulfonyl) -2,3,4,5-tetrahydro-1H-benzorb1azepine-4-carboxylic acid ester To a 2,3,4,5-tetrahydro-1 - [(4-methylphenyl) sulfonyl] -5-oxo-1 H-benzazepine-4-carboxylate solution (4.67 g, 12.1 mmol, CAS 54620-98-3; US 6,369,110; GR Proctor et al., J. Chem. Soc. Perkin Trans 1 1972, 14, 1803-1808) in DMF (24 mL) was added K2CO3 (25.0 g, 18.1 mmol) .The resulting suspension was treated with Ethyl 4-bromobutyrate (1.90 mL, 13.3 mmol) while stirring mechanically under a nitrogen atmosphere at room temperature After 18 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and warmed by addition NCI 1 N aqueous (30 mL) The resulting layers were separated and the organic layer was extracted sequentially with saturated aqueous NaHCO 3, water and brine The organic extract was dried over anhydrous MgSO 3 and concentrated in vacuo. By means of or column chromatography on silica gel eluting with ethyl acetate / hexanes (3: 7) to produce 4- (3-ethoxycarbonyl-propyl) -5-oxo-1- (toluene-4-sulfonyl) ethyl ester. -2,3,4,5-tetrahydro-1 H -benzo [b] azepine-4-carboxylic acid as an oil.

Step B: Ethyl 4- (3-ethoxycarbonyl-propyO-1-o.oluen-4-sulfonyl) -2,3,4,5-tetrahydro-1H-benzo [blazepine-4-carboxylic acid ethyl ester The compound prepared as in step A above, (4.76 g, 9. 48 mmoles) was dissolved in dry 1,2-dichloroethane (45 mL), cooled to 5 ° C, and then treated with trifluoroacetic acid (1.3 mL), BF3 Et20 (1.4 mL), anhydrous methanesulfonic acid (3.2 mL) and triethylsilane (5.7 mL). The reaction was allowed to warm slowly to room temperature for 18 hours. The reaction was cooled to 5 ° C and cautiously warmed with saturated aqueous NaHC 3 (100 mL). The reaction mixture was extracted with ethyl acetate (100 mL) and the ethyl acetate extract was extracted with saturated aqueous NaHCO 3.water, brine (2x), dried over Na 2 SO 4, and concentrated in vacuo to yield an oil. The oil was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (17: 3) to yield 4- (3-ethoxycarbonyl-propyl) -1- (to-4-sulfonyl) -ethyl ethyl ester. -2,3,4,5-tetrahydro-1 H -benzo [b] azepine-4-carboxylic acid as a colorless oil.

Step C: 1- (4-methylphenyl) sulfonyl) -1, 2,3,4-tetrahydro-2'-oxospiro [4H-1-benzazepin-4,1'-cyclopentano1-3'-carboxylic acid ethyl ester The compound prepared as in step B above, (2.43 g, 4.98 mmol) was dissolved in toluene (25 mL) and treated with potassium tert-butoxide (0.843 g, 7.52 mmol) at room temperature. After 1 hour, the reaction mixture was warmed with aqueous 0.5 N HCl (30 mL) and extracted with ethyl acetate (30 mL). The ethyl acetate extract was washed twice with water, NaHCO. saturated aqueous, water, brine, dried over Na2S04 anhydrous and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (4: 1) to yield 1- (4-methylphenylisulfonyl) -1,2,3,4-tetrahydro-2 ' -oxospiro ^ Hl-benzazepin ^ .l'-cyclopentanj-S'-carboxylate ethyl as a solid.

Step D 1 - (4-methylphenylsulfonyl) -1,2,3,4-tetrahydro-2'-hydroxyspiroyl-4H-1-benzazepin-4,1 '-cyclopentan-3'-carboxylic acid ethyl ester The compound prepared as in step C above, (2.10 g, 5.0 mmol) was dissolved in ethanol (20 mL) at room temperature and treated with NaBH4 (0.19 g, 5.0 mmol), evolution of gas was observed. The resulting suspension was stirred for 30 minutes, concentrated in vacuo, and diluted with ethyl acetate. The resulting suspension was cautiously warmed by the addition of aqueous 1 N HCl (30 mL) and stirred for 5 minutes. The layers were separated and the organic layer was extracted with saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4, and concentrated in vacuo to yield 1- (4-methylphenyl) sulfonyl) -1, 2,3,4- Tetrahydro-2'-hydroxyspiro [4H-1-benzazepin-4,1'-cyclopentan] -3'-carboxylic acid ethyl ester as a white solid.

Step E: 1- (4-methylphenyl) sulfonyl) -1, 2,3,4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spiroy4H-1-benzazepin-4,1' -cyclopentan-3 ' ethyl-carboxylate The compound prepared as in step D above (0.415 g, 0.94 mmol) was combined with 2,6-lutidene (0.657 mL, 5.64 mmol) in dry dichloromethane (10 mL) and treated with iod-butyldimethylsilyl trifluoromethanesulfonate. (0.648 mL, 2.82 mmol) while stirring under an argon atmosphere at room temperature. After 20 minutes, the reaction was quenched by the addition of saturated aqueous NaHCO3. The layers were separated and the organic layer was extracted with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (9: 1) to yield 1- (4-methylphenyl) sulfonyl) -1, 2,3,4-tetrahydro-2 '- ( tert-butyldimethylsilyloxy) spiro [4H-1-benzazepin-4,1 '-cyclopentan] -3'-carboxylic acid ethyl ester as a syrup.

Step F: 1,2,3,4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spiroy-4H-1-benzazepin-4,1'-cyclopentan-3'-carboxylate ethyl The compound prepared as in step E above (0.309 g, 0.55 mmol) was dissolved in anhydrous methanol (10 mL) and combined with Turning material of magnesium (0.267 g, 11 mmol) in a sealed tube and heated while stirring magnetically at 65 ° C for 18 hours. The reaction was cooled to room temperature, filtered through a filtration agent, and concentrated in vacuo. The residue was triturated 3 times with ethyl acetate and the combined ethyl acetate triturations were filtered through the filtration agent. The filtrate was extracted twice with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to yield 1, 2,3,4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spyr [4H-1-benzazep] Ethyl n-4,1'-cyclopentan] -3'-carboxylate as a syrup.

Step G: 1-I4- .. H, 1'-biphenyl-2-ylcarbonyl) amino-benzoin-1.2.3.4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spiror4H-1-benzazepin-4,1' -cyclopentan- Ethyl 3'-carboxylate To a suspension of 4 - [([1,1'-biphenyl] -2-ylcarbonyl) amino benzoic acid (0.187g, 0.59 mmol, CAS 168626-74-2, WO 0132639) in dichloromethane ( 2 mL) was added? /,? / - dimethylformamide (0.02mL) thionyl chloride (0.086 mL, 1.18 mmol) while stirring at room temperature under an argon atmosphere. After 18 hours, the resulting solution was concentrated in vacuo, dissolved in dry toluene, concentrated in vacuo, and dissolved in dichloromethane (2 mL). The resulting solution of acid chloride was added dropwise to a solution of the compound prepared as in step F above (0.19 g, 0.47 mmole), triethylamine (0.41 mL, 2.95 mmole), and N, N-dimethylformamide (0.02mL) in dichloromethane (2 mL) while stirring at room temperature. After 72 hours, the reaction mixture was quenched with saturated aqueous NaHCO 3 and extracted with ethyl acetate. The ethyl acetate layer was extracted with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (7: 3) to give 1- [4 - [([1,1-biphenyl] -2-ylcarbonyl) amino] benzoyl] - 1, 2,3,4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spiro [4H-1-benzazepin-4,1'-cyclopentan] -3'-carboxylate as a glass.

Step H: Acid 1-r4-r (ri. 1'-biphenyl-2-ylcarbonyl) amino-1-benzoin-2,3,4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spiror-4H-1-benzazepin-4.1' -cyclopentan-3'-carboxylic acid The compound prepared as in step G above (0.250 g, 0.36 mmol) was combined with potassium hydroxide (0.071 g, 1.08 mmol) in ethanol (20 mL) and heated to reflux while stirring under a nitrogen atmosphere. After 18 hours, the reaction mixture was concentrated in vacuo, dissolved in water, adjusted to pH 2 with aqueous 1 N HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous Na 2 SO 4, and concentrated in vacuo to yield 1- [4 - [([1,1-biphenyl] -2-ylcarbonyl) amino] benzoyl] -1 acid. , 2,3,4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spiro [4H-1-benzazepin-4,1'-cyclopentan] -3'-carboxylic acid as a solid.

Step I: 1-r4-r (Ri, 1'-phenyl-1-2-ylcarbonyl) amino-1-benzoyl-N-r2- (dimethylammon) ethyl-1, 2,3,4-tetrahydro-2 '- ( tert-butyldimethylsilyloxy) spyr [4H-1-benzazepin-4,1'-cyclopentan-3'-carboxamide The compound prepared as in step H above (0.234 g, 0.35 mmol) and? / - methylmorpholine (0.106) mL, 0.97 mmol) was dissolved in tetrahydrofuran (5 mL) and treated dropwise with isopropyl chloroformate (0.048 mL, 0.37 mmol) while stirring under a nitrogen atmosphere at room temperature. After 30 minutes, a solution of N, N-dimethylethylenediamine- (0.062 mL, 0.58 mmol) and N-methylmorpholine (0.106 mL, 0.97 mmol) in tetrahydrofuran (0.5 mL) was added, and the reaction mixture was stirred for 1 hour. hour. The reaction was warmed by the addition of water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with water, brine, dried over anhydrous Na 2 SO 4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-20% methanol / NH OH (99: 1) in dichloromethane for 60 minutes to produce 1- [4 - [([1.1] biphenyl] -2-ylcarbonyl) amino] benzoyl] -N- [2- (dimethylamino) ethyl] -1,2,3,4-tetrahydro-2 '- (tert-butyldimethylsilyloxy) spiro [4H-1-benzazepine] -4,1'-cyclopentan] -3'-carboxamide as a solid.

Step J: 1-r4-r (Ri. 1'-biphenin-2-ylcarbonyl) amnolbenzoin-N-r2- (d-methylamino) ethyl1-1, 2,3,4-tetrahydro-2'-hydroxyspyr 4H-1-benzazepin-4,1'-cyclopentan-3'-carboxamide A solution of the compound prepared as in step I above (0.097 g, 0.13 mmol) in tetrahydrofuran (5 mL) was treated with tetrabutylammonium fluoride 1 M in tetrahydrofuran (0.26 mL, 0.26 mmol) and stirred for 2.5 hours at room temperature under a nitrogen atmosphere. The reaction mixture was partitioned between water and ethyl acetate and the ethyl acetate extract was washed with water, brine, dried over Na 2 SO and concentrated in vacuo to give a 1- [4 - [([1.1] 'biphenyl] -2-alkylcarbonyl) amino] benzoyl] -N- [2- (dimethylamino) ethyl] -1,2,3,4-tetrahydro-2'-hydroxyspiro [4H-1-benzazepin- 4,1'-cilcopentan] -3'carboxamide crude as a solid.

Step K: 1-r4-r (ri .1'b¡fen¡n-2-lcarbonyl) amino-benzoyl-N-r2- (d-methylamino) etn-1, 2,3,5-tetrahydro -2'-oxospiro [4H-1-benzazepin-4,1'-cyclopentan-3'-carboxamide The crude compound from step J (0.065 g, 0.103 mmol) was dissolved in dry dichloromethane (5 mL) and treated with periodinone Dess-Martin (0.065 g, 0.15 mmole) while stirring at room temperature under an argon atmosphere. After 30 minutes, the reaction was warmed by the addition of 20% (w / w) Na 2 S 2 O 3 in saturated aqueous NaHC 3 (total 5 ml) and stirred for 15 minutes. The reaction mixture was extracted twice with ethyl acetate (15 mL) and the combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with dichloromethane / methanol / NH 4 OH (92: 7.92: 0.08) to afford the title compound as a white solid. 1 H NMR (300 MHz, CDCl 3) d 1.45-1.65 (m, 4H), 2.15-2.60 (overlap m, 6H), 2.30 (s, 6H), 2.78 (dd, 1 H, J = 12.7, 12.7 Hz), 3.25-3.70 (overlap m, 3H), 5.13 (d, 1H, J = 12.7 Hz); 6.63 (d, 1 H, J = 7.4 Hz), 6.90-7.70 overlap 16H) MS (ES) m / z 629 (MH) + EXAMPLE 21 1-f 4 -f (f 1, 1 '-biphenin-2-ylcarbonyl) amino-1-benzonip-N-r 2 - (dimethylamino) etn-1, 2,3,5-tetrahydro-2'-hydroxyspirom F 4 H -1 - benzazapin-4.1 '-cyclopentanl-3'-carboxamide 1 - . 1 - [4 - [([1, 1 '-biphenl] -2-ylcarbonyl) amino] benzonyl] -N- [2- (dimethylamino) ethyl] -1, 2,3,5-tetrahydro-2' -hydroxyspiro [4H-1-benzazepin-4,1 '-cyclopentan] -3'-carboxamide was prepared according to the procedure described in example 20 above, with the substitution of suitably substituted reagents, to produce the crude product, which was purified by preparative thin layer chromatography on silica gel eluting with dichloromethane / methanol // NH 4 H H (92: 7.92: 0.08) to afford the title compound as a white solid. 1 H NMR (300 MHz, CDCl 3) d 1.15-1.30 (m, 1 H), 1.30-1.50, (m, 1 H), 1.60-2.10 (m, 2H), 2.20-2.90 (overlap m, 7H), 2.37 (s, 6H), 3.17 (d, 1H, J = 13.2 Hz), 3.50-3.95 (overlap m, 3H), 4.95 (d, 1 H, J = 12.7 Hz); 6.89 (d, 1H, J = 7.3 Hz), 6.70-7.95 (overlap m, 16H) MS (ES) m / z 631 (MH) + EXAMPLE 22 N-r4-r (1, 2,3,5-tetrahydro-2'-oxospirof4H-1-benzazepin-4,1'-cyclopentanl-1-iDcarbonylIfenill-FI A '-bifeniH-2 -carboxamide Step A: 1- (4-methylphenyl) sulfonip-1.2.3.4-tetrahydrospyrro-4H-1-benzazepin-4,1'-cyclopen'l-2'-one The compound prepared as in step C of example 20 above, (6.70 g, 15.2 mmol) was combined with ethanol (23 mL), acetic acid (23 mL) and 6N aqueous HCl (23 mL) and heated to reflux while stirring for 2.5 hours. at room temperature and concentrated in vacuo to yield 1- (4-methylphenyl) sulfonyl) -1,2,3,4-tetrahydrospiro [4H-1-benzazepin-4,1'-cyclopen] -2'-one as a solid.

Step B: 1.2.3.4-tetrahydrospiro [4H-1-benzazepin-4.1'-cyclopen1-2-one The compound prepared as in step A above (0.50 g, 1.35 mmol) was dissolved in anhydrous methanol (27 mL) and was combined with magnesium turning material (0.656 g, 27 mmol) and heated to reflux while stirring magnetically under an argon atmosphere for 18 hours. The reaction was cooled to room temperature, filtered through a filtration agent, and concentrated in vacuo. The residue was triturated 3 times with ethyl acetate and the combined ethyl acetate triturations were filtered through a filtration agent. The filtrate was extracted twice with brine, dried over anhydrous NaSO4, and concentrated in vacuo to yield 1, 2,3,4-tetrahydrospiro [4H-1-benzazepin-4,1'-cyclopen] -2-ona as a solid.

Step C: N-4-r (1, 2,3,5-tetrahydro-2'-oxospiror4H-1-benzazepin-4,1, -cyclopentan-1-yl) carboninfenin-ri. 1'-difen n-2-carboxamide To a suspension of 4 - [([1,1'-biphenyl] -2-ylcarbonyl) amino] benzoic acid (0.444 g, 1.40 mmol, CAS 168626-74-2, WO 0132639) in dichloromethane ( 10 mL) was added N, N-dimethylformamide (0.1 mL) and thionyl chloride (0.204 mL, 2.80 mmol), while stirring at room temperature under an argon atmosphere. After 18 hours, the resulting solution was concentrated in vacuo, dissolved in dry toluene, concentrated in vacuo, and dissolved in 10 mL of dichloromethane. The resulting acid chloride solution was added dropwise to a solution of the compound prepared in step B above (0.295 g, 1.12 mmol) and triethylamine (0.470 ml, 3.37 mmol) in dichloromethane (10 mL) while stirring at room temperature . After 24 hours, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was extracted with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with linden acetate / hexane (11: 9) to afford the title compound as a white solid.

? NMR (300 MHz, DMSO-d6) d 1.40-1.70 (m, 2H), 1.70-2.00, (m, 2H), 2.20-2.50 (m, 2H), 2.59 (d, 1 H, J = 13.8 Hz) , 2.72 (dd, 1 H, J = 13.1, 13.1 Hz), 2.97 (d, 1H, J = 13.8 Hz), 4.77 (d, 1 H, J = 13.1 Hz), 6.69 (d, 1 H, J = 7.0 Hz), 6.90 -7.70 (overlap m, 16H) MS (ES) m / z 515 (MH) + EXAMPLE 23 N-r4-r (1, 2,3,5-tetrahydro-2'-hydroxyspiroF4H-1-benzazepin-4,1'-cyclopentanl-1-yl) carbonylphenylH1, 1'-biphenyl-2-yl carboxamide The compound prepared from example 22 above (0.025 g, 0.048 mmol) was dissolved in methanol (1 mL) and treated with sodium borohydride (0.010 g, 0.288 mmol) with stirring at room temperature under an argon atmosphere. After 24 hours, the reaction mixture was concentrated in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was separated, concentrated in vacuo and purified via preparative thin layer chromatography on silica gel eluting with dichloromethane / ethanol (97.5: 2.5) to generate the title compound as a white solid. 1 H NMR (300 MHz, CD 3 OD) d 1.00-3.60 (overlap m, 2 H), 3.80-3.90 (m, 1 H), 4.60-4.90 (m, 1 H); 6.50-6.80 (m, 1 H), 6.90-7.70 (overlap m, 16 H). MS (ES) m / z 517 (MH) + EXAMPLE 24 N-r3-methoxy-4-r (1 .2.3,5-tetrahydro-2, -oxoespiroF4H-1-benzazepin-4 .V cyclopentan1-1- il) carbonillfenH? -2-chloro-5-fluorobenzamide Step A: 4- (2-chloro-5-fluoro-benzoylamino) -3-methoxy-benzoic acid A suspension of 2-chloro-4-fluorobenzoic acid (3.15 g, 18.0 mmol) in thionyl chloride was stirred. (15 mL) at room temperature under an argon atmosphere for 18 hours. The reaction mixture, which now appears as a solution, was concentrated in vacuo and dissolved in dichloromethane (10 mL). The resulting solution of acid chloride was added dropwise at 5 ° C to a solution of methyl 3-methoxy-4-aminobenzoate (3.26 g, 18.0 mmol) and triethylamine (5.0 mL, 36 mmol) in dichloromethane (25 mL) with stirring under an argon atmosphere. The reaction mixture was allowed to warm slowly to room temperature for 18 hours. Water was added and the reaction mixture was stirred for 5 minutes. The layers were separated and the organic layer was extracted sequentially with 1N aqueous HCl, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4 and concentrated in vacuo to generate 4- (2-chloro-5-fluoro-benzoylamino) -3. -Methyl-methoxybenzoate. This material was suspended between tetrahydrofuran / water (1: 1) (40 mL total), treated with sodium hydroxide monohydrate (0.755 g, 18.0 mmol) and stirred at room temperature for 18 hours. The reaction mixture was acidified to pH 2 with 1 M aqueous KHSO4 and the resulting precipitate was isolated by filtration and recrystallized from a mixture of ethanol and ethyl acetate to generate 4- (2-chloro-5-fluoro- benzoylamino) -3-methoxy-benzoic acid as a white solid.

Step B: N-r3-methoxy-4-r (1, 2,3,5-tetrahydro-2'-oxospiror4H-1-benzazepin-4,1'-cyclopentanM-1) carbonl] phenyl-2 chloro-5-fluorobenzamide A suspension of 4 (2-chloro-5-fIuoro-benzoylamino) -3-methoxy-benzoic acid, prepared as in step A above (1.07 g, 3.31 mmol) in dichloromethane (25 mL) was treated with thionyl chloride (25 mL) and heated to reflux under an argon atmosphere for 18 hours. The reaction mixture was concentrated in vacuo and dissolved in dichloromethane (50 mL). The resulting solution of acid chloride was added dropwise at 5 ° C to a solution of compound prepared as step B of Example 22 (0.640 g, 2.97 mmol), triethylamine (2 mL), and? /,? / - dimethylformamide (0.25 mL) in dichloromethane (25 mL) with stirring under an argon atmosphere. After 18 hours, the reaction mixture was extracted with NaHCO. watery saturated.

The organic layer was extracted with aqueous 1M KHS04, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with a gradient of -5% methanol in dichloromethane over 60 minutes to generate the title compound as a white solid. 1 H NMR (300 MHz, CDCl 3) d 1.50-1.65 (m, 2H), 1.65-1.80 (m, 2H), 1.80-2.00 (m, 2H), 2.04 (dd, 1 H, J = 13.8 Hz), 2.80 (dd, 1 H, J = 12.4, 12.4 Hz), 3.30 (d, 1 H, J = 13.9 Hz), 3.70 (s, 3H), 5.03 (d, 1 H, J = 13.8 Hz), 6.60-7.30 (overlap m, 7H), 7.70-7.85 (m, 1H), 8.26 (d, 1 H, J = 8.3 Hz), 8.60 (s, 1 H) EM (ES) m / z 521 (MHf EXAMPLE 25 Ethyl 4- (3-ethoxycarbonyl-propyl) -1- (toluene-4-sulfoniD-2,3A5-tetrahydro-1H-benzorb-1azepin-4-carboxylic acid ethyl ester A series of experiments were carried out in the conversion of 4- (3-ethoxycarbonyl-propyI) -5-oxo-1- (toluene-4-sulfonyl) -2,3,4,5-tetrahydro-1 H ethyl ester -benzo [b] azepine-4-carboxylic acid 4- (3-ethoxycarbonyl-propyl) -1- (toluene-4-sulfonyl) -2,3,4,5-tetrahydro-1H-benzoic acid ethyl ester [ b] azepine-4-carboxylic acid. The experiments were carried out in an automated reactor system using 12 reactors. The experiments were completed in accordance with the general procedure described below. The experimental conditions were selected based on a quadratic algorithmic design. Reactive agents, including starting materials were prepared by diluting with solvent at the concentration listed in Table 1.

TABLE 1 Parts of 4- (3-ethoxycarbonyl-propyl) -5-oxo-1- (toluene-4-sulfonyl) -2,3,4,5-tetrahydro-1H-benzo [b] azepin ethyl ester were dissolved. 4-carboxylic acid (SM) in dichloromethane and trifluoromethylbenzene to produce a solution containing 50 mg of SM / ml (0.1 mmol / ml) of solution. 2 ml of the appropriate solution (0.2 mmol of SM) was placed in the individual reactors and stirred for 5 minutes at 0 ° C. The selected amounts of trifluoroacetic acid, boron trifluoride etherate and methanesulfonic acid were added to each reaction. The reaction was treated with the selected amount of triethylsilane. The reaction was then warmed to 23 ° C, maintained at that temperature for 30 minutes and sampled. The temperature was maintained at 23 ° C for an additional 30 minutes and then cooled to 0 ° C. The temperature was maintained at 0 ° C until all the samples could be manually removed from the equipment. The conditions for each experiment (including equivalents of CH3SO3H, trifluoroacetic acid (TFA), BF3 »etherate and triethylsilane and the selected solvent used) were listed in Table 2 below.

TABLE 2 Experimental conditions The study as listed in table 2 is completed in two parts. In Table 3 the distinction between the two runs was made by using an "A" after the reactor number. The individual experiments were sampled and transferred for analysis by chromatography to determine the percent yield, and the results are listed in Table 3. Analysis of all samples was performed on a Super ODS column using 0.1% trifluoroacetic acid in water. 0.1% trifluoroacetic acid in acetonitrile gradient from 55% acetonitrile to 65% acetonitrile in 10 minutes.

TABLE 3 EXAMPLE 26 Diethyl amine salt of (4R) -1-F4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzo-p-1,2,3,5-tetrahydro-espyror4H- 1-benzazepin-4,1 > - F21cyclopenten1-3'-carboxylic acid A solution of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1] '- [2] cyclopentene] -3'-carboxylic acid (1.65 g, 3.01 mmol) and diethylamine (0.22 g, 3.01 mmol) in 20 ml of isopropyl acetate and 1 ml of methanol was heated to reflux to distill off methanol. Then water (0.108 g, 6.02 mmol) was added. The clear solution was cooled to 60 ° C and the solid salt precipitated. The resulting solution was then cooled to room temperature and the solid was collected by filtration and dried in a vacuum oven at 55 ° C. 1 H NMR of the isolated salt indicated that the salt had a one-to-one molar ratio of (4R) -1- [4- (2-cyoro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1,3,3, 5, tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid and diethylamine without some residual solvents. ? NMR (DMSO-d6) 9.76 (s, 1 H), 7.85 (d, J = 8.5 Hz, 1 H), 7.60 to 6.65 (m, 9H), 6.37 and 5.93 (ss, 1 H, rotamers), 4.82 -4.58 (m, 1 H), 3.57 (s, 3H), 3.35 (t, J = 13.3 Hz, 1 H), 3.03 to 2.78 (m, 1 H), 2.67 (q, J = 7.2 Hz, 4H) , 2.75 to 2.33 (m, 3H), 2.08 to 1.80 (m, 2H), 1.73 to 1.33 (m, 2H), 1.07 (t, J = 7.2 Hz, 6H). p.f .: 159.7-160.4 ° C Solubility in water: > 10 mg / ml. Chemical analysis for: C34H37CIFN3? 5-0.2H2 ?: Calculated: C, 65.27; H, 6.03; N, 6.72; F, 3.04; Cl, 5.67; KF, 0.58 Found: C, 65.29; H, 5.69; N, 6.62; F, 3.12; Cl, 5.76; KF, 0. 53 EXAMPLE 27 (4R) -1-F4- (2-Chloro-5-fluorobenzoyl) amino-3-methoxybenzoin-1, 2,3,5-tetrahydro-spiro 4H-1-benzazepin-4,1 'piperazine salt - F21cyclopenten1-3'-carboxylic acid A solution of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1] '- [2] cyclopentene] -3'-carboxylic acid (2.78 g, 5.06 mmol) and piperazine (0.22 g, 2.53 mmol) in 30 ml of isopropyl acetate and 6 ml of methanol was heated to reflux to distill off methanol. Then water (0.091 g, 5.06 mmol) was added. The clear solution was cooled to 72 ° C and the solid salt precipitated. The resulting solution was cooled to room temperature and the solid collected by filtration and dried in a vacuum oven at 55 ° C. 1H NMR of the isolated salt indicated that the salt was in a molar ratio of two to one of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1 acid, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid and piperazine with an equivalent of 0.36 mol of isopropyl acetate. 1 H NMR (DMSO- 6) 9.76 (s, 1 H), 7.85 (d, J = 8.5 Hz, 1 H), 7.61 to 6.68 (m, 9H), 6.52 and 6.02 (ss, 1 H, rotamers), 4.82-4.58 (m, 1 H), 3.57 (s, 3H), 3.35 (t, J = 13.3 Hz, 1 H), 3.03 to 2.33 (m, 4H), 2.73 (s, 4H), 2.08 to 1.80 ( m, 2H), 1.73 to 1.33 (m, 2H). P.f .: 159-161 ° C.

Chemical analysis for C32H31CIFN3O5.0.36C5H10? 2.0.45H2O Calculated: C, 63.74; H, 5.62; N, 6.60; F, 2.99; Cl, 5.57; KF, 1.28 Found: C, 63.60, H, 5.35; N, 6.51, F, 3.12, Cl, 5.77; KF, 1. 28 EXAMPLE 28 (4R) -1-r4- (2-Chloro-5-fluorobenzoyl) amino-3-methoxybenzoin-1,2,3,5-tetrahydro-spiro 4H-1-benzazepinAl acid 1-2-hydroxyethyl) pyrrolidone salt ^ lcyclopentenl-S'-carboxylic acid A solution of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1,2,3,5-tetrahydro-spiro [4H-1-benzazepin-4] , 1 '- [2] cyclopentene] -3'-carboxylic acid (2.48 g, 4.51 mmol) and 1- (2-hydroxyethyl) pyrrolidine (1.04 g, 9.02 mmol) in 46 ml of isopropyl acetate and 2 ml of Methanol was heated to reflux to distill and separate the methanol. Then water (0.086 g, 4.51 mmol) was added. The solid salt began to precipitate upon cooling. The solution was cooled to room temperature and the solid (2.47 g) was collected by filtration. 1H NMR of the isolated salt indicated that the salt was in a one-to-one molar ratio of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2, 3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid and 1- (2-hydroxyethyl) pyrrolidine without some residual solvents. 1 H NMR (CD3OD) 8.04 (d, J = 8.3 Hz, 1 H), 7.57 to 6.67 (m, 9H), 6.44 and 6.12 (ss, 1 H, rotamers), 3.81 (t, J = 5.3 Hz, 2H ), 3.63 (s, 3H), 3.45 to 2.94 (m, 3H), 3.28 (m, 4H), 3.20 (t, J = 5.3 Hz, 2H), 2.85 to 2.48 (m, 3H), 2.18 to 1.89 ( m, 2H), 2.04 (m, 4H), 1.83 to 1.45 (m, 2H). p.f .: 187.5-188.4 ° C Solubility in water: > 20 mg / mL. Chemical analysis for: C3oH26CIFN2? 5- »C6H-? 3NO» H20 Calculated: C, 63.38; H, 6.06; N, 6.16; Cl, 5.20; F, 2.78 Found: C, 63.32, H, 5.57; N, 5.95, Cl, 5.25; F, 3.17. Although the foregoing description shows the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all the usual variations, adaptations and / or modifications that come to mind within the scope of the invention. of the following claims and their equivalents.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A process for the preparation of a compound of formula (!) wherein it is selected from the group consisting of aryl and heteroaryl; provided that the heteroaryl group does not contain a nitrogen atom; a is an integer from 1 to 3; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, phenyl, substituted phenyl, alkylthio, arylthio, alkylsulfoxide, arylsuiphoxide, alkylsulfone and arylsulfone; -R2-R3- is selected from the gr and R10 is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl and - (B) 0 -? - G- (E) or -? - (W)? - 3; wherein B is selected from (CH2)? - 3, NH or O; G is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl; E is selected from -0-, -S-, - NH-, - (CH2) 0-3-N (R11) C (O) - or - (CH2) or -3-C (O) NR11-; wherein R11 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; each W is independently selected from hydrogen, alkyl, substituted alkyl, amino, substituted amino, alkylthiophenyl, alkyl sulphoxydiphenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; X is selected from the group consisting of CH, CH2, CHOH and C (O); represents a double or single link; with the proviso that when R1 is iodo, bromo alkylthio, arylthio, alkylsulfone or arylsulfone, then it is a double bond; n is an integer from 1 to 3; b is an integer from 1 to 2; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, phenyl and substituted phenyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aldehyde, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, - (CH2) kNZ1Z2 and -C (0) NZ1Z2; where k is an integer from 1 to 4; Z1 and Z2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aminocarbonyl or substituted aminocarbonyl; alternatively Z1 and Z2 are taken together with the N atom to which they are attached to form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof; which comprises reacting a compound of formula (II) wherein -R2a-R2b is selected from the group consisting of -NH-CH2-NH- with a compound of formula (XV) wherein T1 is Cl, Br or F; in the presence of a base capable of neutralizing HT1; in a non-alcoholic organic solvent or a mixture of a non-alcoholic organic solvent and water, to generate the corresponding compound of formula (I).
2. The process according to claim 1, further characterized in that T1 is Cl.
3. The process according to claim 1, further characterized in that R5 in the compound of formula (II) is carboxyl, which further comprises protecting the carboxyl by reacting the compound of formula (II) with TMSCI on site. according to claim 1, it is phenyl, X is -CH2-, R5 is -C02H, n is 1, b is 0, -R2-R3- is 4-N- CH2- | - and R10 is OT ARIO 5. - The method according to claim 4, further characterized in that the base capable of neutralizing HT1 is an organic tertiary amine base. 6. The process according to claim 5, further characterized in that the compound of formula (II) reacts with the compound of formula (XV) in a non-alcoholic organic solvent. 7. The process according to claim 6, further characterized in that the organic tertiary amine base is pyridine and the non-alcoholic organic solvent is toluene. 8. The process according to claim 7, further characterized in that the compound of formula (II) reacts with the compound of formula (XV) at a temperature in the range of between about 0 ° C and around room temperature. 9. A compound prepared according to the method according to claim 1. 10. A compound prepared according to the method according to claim 4. 11. - A process for the preparation of a compound of formula (II) wherein it is selected from the group consisting of aryl and heteroaryl; provided that the heteroaryl group does not contain a nitrogen atom; a is an integer from 1 to 3; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, phenyl, substituted phenyl, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone; -R2-R3- is selected from the group consisting of -NH-CH2- and -CH2-NH-, -R2a-R3a- is selected from the group consisting of -NH-CH2- and -CH2-NH-; X is selected from the group consisting of CH, CH2, CHOH and C (O); represents a double or single link; with the proviso that when R1 is iodo, bromo alkylthio, arylthio, alkylsulfone or arylsulfone, then it is a double bond; n is an integer from 1 to 3; b is an integer from 1 to 2; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, phenyl and substituted phenyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aldehyde, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, - (CH2) kNZ1Z2 and -C (0) NZ1Z2; where k is an integer from 1 to 4; Z1 and Z2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aminocarbonyl or substituted aminocarbonyl; alternatively Z1 and Z2 are taken together with the N atom to which they are attached to form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof; which comprises (IX) reacting a compound of formula (VII), where p is an integer from 0 to 1, q is an integer from 1 to 2, with the proviso that when p is 0, then q is 2 and when p is 1 then q is 1, PG1 is a nitrogen protecting group and A2 is lower alkyl; with a compound of formula (VIII) wherein Q2 is a leaving group and A3 is lower alkyl; in the presence of a base capable of deprotonating an alpha proton to the ketone in the compound of formula (VII); in an aprotic solvent, to produce the corresponding compound of formula (IX); reducing the compound of formula (IX) to produce the corresponding compound of formula (X); reacting the compound of formula (X) in the presence of a base capable of deprotonating an alpha proton to the C02A3 substituent; in an organic solvent that does not prevent the deprotonation of an alpha proton to the C02A3 substituent, to produce the corresponding compound of formula (XI); (XI) reducing the compound of formula (XI) to generate the corresponding compound of (Xll); Y reacting the compound of formula (Xll) to generate the corresponding compound of formula (II). 12. The process according to claim 11, further characterized in that ((, is phenyl, X is -CH2-, R5 is -C02H, n is 1, b is 0, and -R2a-R3a- is -NH- CH2- 13. The process according to claim 12, further characterized in that the base capable of deprotonating an alpha proton to the ketone in the compound of formula (VII) is an inorganic base. claim 13, further characterized in that the inorganic base is K2CO3 and the aprotic solvent is DMF 15. The process according to claim 12, further characterized in that the compound of formula (IX) is reduced to the corresponding compound of formula (X ) by reacting the compound of formula (IX) with triethylsilane in the presence of a mixture of TFA, methanesulfonic acid and BF3 * etherate. 16. The process according to claim 15, further characterized in that triethylsilane, TFA, methanesulfonic acid and BF3 * etherate are present in a molar equivalent ratio of 5.0 of triethylsilane at 2.5 TFA at 6.0 methanesulfonic acid to 1.8 of BF3 * etherate. 17. The method according to claim 16, further characterized in that the compound of formula (IX) is reduced to the corresponding compound of formula (X) in dichloroethane. 18. The process according to claim 12, further characterized in that the base capable of deprotonating an alpha proton to the substituent C02A3 is an alkali metal alkoxide. 19. The process according to claim 18, further characterized in that the alkali metal alkoxide is potassium t-butoxide and wherein the organic solvent that does not prevent the deprotonation of an alpha proton to the CO2A3 substituent is toluene. 20. The process according to claim 12, further characterized in that the compound of formula (XI) is reduced to the corresponding compound of formula (Xll) by reacting the compound of formula (XI) with sodium borohydride in ethanol. 21. A compound prepared according to the method according to claim 11. 22. A compound prepared according to the method according to claim 12. 23. - A process for the preparation of a compound of formula (XVa) O G ^ T3 (CH2) 0_3 NH (XVa) O ^ W wherein T3 is selected from the group consisting of Cl, Br and F; G se selects from aryl, substituted aryl, heteroaryl or substituted heteroaryl; W is selected from hydrogen, alkyl, substituted alkyl, amino, substituted amino, alkylthiophenyl, alkylsulphoxydiphenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; which comprises reacting a compound of formula (XX), wherein A4 is alkyl Bottom with a compound of formula (XXI) wherein T2 is Cl, Br or F; in presence of a base capable of neutralizing HT2; in an organic solvent not alcohol, to produce the corresponding compound of formula (XXII); (XXII) hydrolyzing the compound of formula (XXII) to generate the corresponding compound of formula (XXlll); reacting the compound of formula (XXIII) with a reagent capable of converting the -CO2H substituent with the corresponding substituent -C (O) T3; in an inert organic solvent, to generate the corresponding compound of formula (XVa). 24. The method according to claim 23, further characterized in that T3 is Cl. 25.- The process according to claim 24, further characterized in that G is 1- (3-methoxy-phenyl) and W is 1- (2-chloro-5-fluoro-phenyl). 26. - The method according to claim 25, further characterized in that the base capable of neutralizing HT2 is an organic tertiary amine base. 27. The process according to claim 26, further characterized in that the organic tertiary amine base is triethylamine. 28. The process according to claim 27, further characterized in that the non-alcoholic organic solvent is DCM or ethyl acetate. 29. The process according to claim 28, further characterized in that the compound of formula (XX) reacts with the compound of formula (XXI) at a temperature in the range of between about 0 ° C and around room temperature. 30. The process according to claim 25, further characterized in that the compound of formula (XXII) is hydrolyzed to the corresponding compound of formula (XXIII) by reacting the compound of formula (XXII) with water in the presence of base, in a organic solvent. 31. The process according to claim 30, further characterized in that the base is LiOH and the organic solvent is THF. 32. The process according to claim 25, further characterized in that the reagent capable of converting the substituent -C02H to the substituent -C (0) T3 is oxalyl chloride or thionyl chloride. 33. The process according to claim 32, further characterized in that the compound of formula (XXIII) reacts with oxalyl chloride at a temperature in the range of between about 0 ° C and around room temperature. 34. A compound prepared according to the method according to claim 23. 35.- A compound prepared according to the process according to claim 25. 36.- A compound of formula (II) is selected from the group consisting of aryl and heteroaryl; with the proviso that the heteroaryl does not contain a nitrogen atom; a is an integer from 1 to 3; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, phenyl, substituted phenyl, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, phenyl, substituted phenyl, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone; -R2a-R3a- is selected from the group consisting of -NH-CH2- and -CH2-NH-; X is selected from the group consisting of CH, CH2, CHOH, and C (O); represents a single or double bond, with the proviso that when R1 is iodo, bromo, alkylthio, arylthio, alkylsulfone or arylsulfone, then it is a double bond; n is an integer from 1 to 3; b is an integer from 1 to 2; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, phenyl and substituted phenyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aldehyde, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, - (CH2) kNZ1Z2 and -C (0) NZ1Z2; where k is an integer from 1 to 4; Z1 and Z2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, aminocarbonyl or substituted aminocarbonyl; alternatively Z1 and Z2 are taken together with the N atom to which they are attached to form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof. 37. The compound according to claim 36, further characterized in that ^^ is phenyl, X is -CH2-, R5 is -C02H, n is 1, b is 0 and -R2a-R3a- is -NH-CH2- . 38.- The compound according to claim 36, further characterized in that it is selected from 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3' acid. -carboxylic acid or a pharmaceutically acceptable salt thereof. 39. The compound according to claim 36, further characterized in that it is selected from (4R) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cclopenten ] -3'-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound according to claim 36, further characterized in that it is selected from (4S) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten ] -3'-carboxylic acid or a pharmaceutically acceptable salt thereof. 41.- A process for the preparation of (4R) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2-cyclopenten] -3'-carboxylic acid which comprises reacting a mixture Racemic acid 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid with (-) - camphorsulfonic acid. 42. The process according to claim 41, further characterized in that the (-) - camphorsulfonic acid is present in an amount equal to about one equivalent. 43.- The method according to claim 42, further characterized in that 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid Reacts with (-) - camphorsulfonic acid in methanol. 44.- A process for the preparation of (4S) -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid which comprises reacting a racemic mixture of 1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid with (+) - camphorsulfonic acid. 45.- A compound of formula 46. - A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 9. 47.- A pharmaceutical composition that is made by mixing a compound according to claim 9 and a pharmaceutically acceptable carrier. 48. A process for making a pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier. 49.- The use of the compound of claim 9, for preparing a medicament for treating a condition that involves increased vascular resistance and heart failure in a subject in need thereof. 50.- The use as claimed in claim 49, wherein the condition is selected from the group consisting of aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure / heart failure, coronary vasospasm, cardiac ischemia, cirrhosis of the liver, renal vasospasm, renal deficiency, edema, ischemia, stroke, thrombosis, water retention, nephritic syndrome and central nervous system lesions. 51.- The process according to claim 15, further characterized in that the triethylsilane, BF3"Etherate, TFA, and methanesulfonic acid are present in a molar ratio of 3.75 triethylsilane to 2.79 BF3" E.erato at 5.27 TFA to 1.2 acid methanesulfonic 52.- A diethylamine salt of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-] acid benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid, said acid is composed of the formula (la). 53.- The diethylamine salt in accordance with the claim 52, further characterized in that the ratio of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1 - benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid to diethylamine is 1: 1. 54.- Diethylamine salt in accordance with the claim 53, which comprises the following x-ray diffraction peaks: 55. - A piperazine salt of (4R) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin- 4,1 '- [2] cyclopenten] -3'-carboxylic acid and said acid is composed of the formula (la). 56.- The piperazine salt in accordance with the claim 55, further characterized in that the ratio of (4R) -1 - [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1] acid benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid to piperazine is 2: 1. 57.- The piperazine salt in accordance with the claim 56, which comprises the following X-ray diffraction peaks: 58. - A salt of 1- (2-hydroxyethyl) pyrrolidine of (4R) -1 - [4- (2-chloro-5-fluorobenzoyl) amino-3-methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid, said acid is composed of the formula (la) 59.- The 1- (2-hydroxyethyl) pyrrolidine salt according to claim 58, further characterized in that the ratio of (4f?) -1- [4- (2-chloro-5-fluorobenzoyl) amino-3 acid -methoxybenzoyl] -1, 2,3,5-tetrahydro-spiro [4H-1-benzazepin-4,1 '- [2] cyclopenten] -3'-carboxylic acid to 1- (2-hydroxyethyl) pyrrolidine is eleven. 60.- The 1- (2-hydroxyethyl) pyrrolidine salt according to claim 59 comprising the following X-ray diffraction peaks: 61. - A process for preparing the salt according to claim 52, comprising: reacting a compound of formula (la) with diethylamine and separating said salt. 62.- A process for preparing the salt according to claim 55, comprising: reacting a compound of formula (Ia) with piperazine and separating said salt. 63.- A process for preparing the salt according to claim 58, comprising: reacting a compound of formula (la) with 1- (2-hydroxyethyl) pyrrolidine and separating said salt.