WO2013084241A1 - Compounds as inhibitors of renin - Google Patents

Compounds as inhibitors of renin Download PDF

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Publication number
WO2013084241A1
WO2013084241A1 PCT/IN2012/000109 IN2012000109W WO2013084241A1 WO 2013084241 A1 WO2013084241 A1 WO 2013084241A1 IN 2012000109 W IN2012000109 W IN 2012000109W WO 2013084241 A1 WO2013084241 A1 WO 2013084241A1
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piperidine
cyclopropyl
polar isomer
carboxamide hydrochloride
alkyl
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PCT/IN2012/000109
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French (fr)
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Pravin S. Thombare
Jigar N. DESAI
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Cadila Healthcare Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel renin inhibitors of general formula (1), novel intermediates involved in their synthesis, their pharmaceutically acceptable salts and pharmaceutical compositions containing them.
  • the present invention also relates to processes for preparing compounds of general formula (1), their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.
  • the Renin arfgotension aldosterone system is a key regulator of blood pressure (BP) as well as volume and electrolyte in both hypertensive and normotensive individual. Inappropriate activation of the RAAS is an important event/step in hypetension induced cardiovascular disease (CVD) and chronic kidney diseases (CKD). Pharmacological interruption of the RAAS is possible at three major sites, the angiotensin converting enzyme (ACE), the ATI receptor and at the interaction of renin with substrate, angiotensinogen. (Mancia et al, J Hypertension , 2007, 19(6), 1 105; Chobaniau, Hypertension, 2003,42(6), 1206)
  • the biologically active angiotensin II (Ang II) is generated by two step mechanism in the RAAS.
  • the highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the action of less specific ACE.
  • Ang -H is known to work on at least two receptor subtypes called ATI and AT2.
  • ATI seems to transmit most of the known functions of Ang II, the role of AT2 is still unknown.
  • Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases.
  • ACE inhibitors and ATI blockers have been accepted to treat hypertension (Waeber B. et al, "The renin-angiotensin system: role in experimental and human hypertension", in Birkenhager W.
  • ACE inhibitors are used for renal protection (Rosenberg M. E. et al, Kidney International, 1994, 45, 403; Breyer J. A. et al. Kidney International, 1994, 45, S156), in the prevention of congestive heart failure (Vaughan D. E. et al, Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al., Am. J. Med, 1988, 8.4 (Suppl. 3A), 83) and myocardial infarction (Pfeffer M. A. et al, N. Engl. J. Med., 1992, 327, 669).
  • renin inhibitors The rationale to develop renin inhibitors is the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645).
  • the only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin.
  • ACE can also cleave bradykinin besides Ang I and can be by-passed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 1 1, 1 155). In patients, inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Konili Z. H.
  • renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects. Only limited clinical experience (Azizi M. et al., J.
  • the present invention relates to the identification of further renin inhibitors of a non-peptidic- nature and of low molecular weight. Described are orally active renin inhibitors of long duration, of action which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis. So, the present invention describes these non-peptidic renin inhibitors.
  • the aim of the present invention is to improve in- vitro potency and also to overcome some of the problems in the earlier reported renin inhibitors such as problems with pharmacokinetics.
  • the present invention describes a group of novel compounds as renin inhibitors useful for the treatment of cardiovascular events, renal insufficiency and other related diseases.
  • the novel compounds are defined by the general formula (1) below:
  • the compounds of the present invention are useful in the treatment of the human or animal body, by regulating renin levels.
  • the compounds of this invention are therefore suitable for the treatment of cardiovascular events, renal insufficiency other related diseases.
  • the main objective of the present invention thus is to provide novel compounds of general formula (1), . novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures as therapeutic agen
  • compositions containing compounds of general formula (1), their pharmaceutically acceptable salts comprising pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
  • novel compounds of the present invention as blood pressure regulating agents, by administering a therapeutically effective and non-toxic amount of the compounds of formula (1) or their pharmaceutically acceptable compositions to the mammals.
  • novel compounds of the present invention are defined by the general formula (I) below:
  • Ri is optionally substituted Ct.C 6 alkyl, or C3-C7 cycloalkyl groups
  • R 2 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, S and N, wherein when R 2 is substituted, the substituents on the aryl ring or heteroaryl ring comprises of one or more substituents independently selected from the group comprising of OH, CN, NH 2 , halogen, oxo, OCF 3, CF 3, C r C 6 alkyl, OC,-C 6 alkyl, (CH 2 ),.
  • R 3 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, S and N, wherein when R 3 is substituted, the substituents are independently selected from the group comprising of oxo, OH, CN, NH 2 , halogen, OCF 3; OCF 2 H, CF 3j C -C alkyl, OCi-C 6 alkyl, C 3 -C 6 cycloalkyl, OC 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, (CH 2 )i.
  • R 3 represents one of the
  • each of the ring structures may be either unsubstituted or substituted with one, two or three substituents independently selected from the group consist of oxo, OH, CN, NH 2 , halogen, OCF 3, OCF 2 H, CF 3, Ci-C 6 alkyl, OC,-C 6 alkyl, C 3 -C 6 cycloalkyl, OC 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, d-C 6 alkoxy, (CH 2 )i- 6 OCi-C 6 alkyl, O- (CH 2 )o- 4 0C,-C 6 alkyl, C(0)NHC r C 6 alkyl, NHC(0)C C 6 alkyl, S(O) 0 .
  • substituents independently selected from the group consist of oxo, OH, CN, NH 2 , halogen, OCF 3, OCF 2 H, CF 3, Ci-C 6 alkyl, OC,-
  • R 3 is selected from the group comprising of
  • each of the ring structures may be either unsubstituted or substituted with one, two or three substituents independently selected from the group comprising of oxo, OH, CN, NH 2 , halogen, OCF 3i OCF 2 H, CF 3; C,-C 6 alkyl, OC C 6 alkyl, C 3 -C 6 cycloalkyl, OC 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C,-C 6 alkoxy, (CH 2 ), -6 OC r C 6 alkyl, 0-(CH 2 )o.
  • Ri and R 2 together with the nitrogen atom to which they attached may form a saturated, unsaturated or partly saturated single or fused heterocyclic ring which may optionally contain one or more additional heteroatoms selected from N, O or S or may comprise an -SO- or an -S0 2 -group.
  • the heterocyclic ring formed by Rj and R 2 as defined above further comprises one or more nitrogen atom, such nitrogen atom may optionally be substituted with optionally substituted groups selected from Ci-C 8 alkyl, Ci-Cg alkanoyl, optionally substituted aryl or heterocyclic group.
  • the heterocyclic ring may further be substituted with one or more optionally substituted aryl or heterocyclic group or the groups selected from haloalkyl, haloalkoxy, Q-Cg alkyl, OCi-C 6 alkyl, (CH ⁇ Od-Ce alkyl, O-(CH 2 ) 0 - 4 OC 1 -C 6 alkyl, C(0)NHd-C & alkyl, NHC(0)d-C 6 alkyl, S(O) 0?2 C,-C 6 alkyl,
  • the preferred substituents may be selected from halogen, C,-C 6 alkyl, OC,-C 6 alkyl, (CH 2 ),. 6 OCi-C 6 alkyl, O-(CH 2 ) 0 -4OCi-C 6 alkyl, groups.
  • R 4 at each occurrence is independently selected from the group comprising of hydrogen, C1-C4 alkyl group C 1-C4 haloalkyl, C 3 -C 7 cycloalkyl groups.
  • heterocycle or “heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms & also contains from 1 to 4 hetero atoms independently selected from the group consisting of N, O and S and. including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • heterocycle as used in the specification includes both aromatic and non-aromatic single or fused cyclic system containing at least one heteroatom selected from N, O and S.
  • the total number of S and O atoms in the heterocycle is not more than 1.
  • aromatic heterocyclic system is intended to mean a stable 5- to 7,-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH- indazolyl, indolenyl, indolin
  • Suitable substituents wherever applicable if not specifically defined elsewhere, includes, but are not limited to the following radicals, alone or in combination with other radicals: hydroxyl, oxo, halo, thio, nitro, amino, alkyl, alkoxy, haloalkyl or haloalkoxy groups;
  • radicals described above may be selected from:
  • alkyl used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, «-propyl, i ' so-propyl, n-butyl, sec-butyl, t-butyl, amyl, /-amyl, ' w-pentyl, n- . hexyl, and the like;
  • alkynyl used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons, such as ethynyl, 1 -propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.
  • alkynyl includes di- and tri-ynes;
  • alkoxy used herein, either alone or in combination with other radicals, denotes a radical alkyl, as defined above, attached directly to an oxygen atom, such as methoxy, ethoxy, rc-propoxy, wo-propoxy, «-butoxy, -butoxy, wo-butoxy, pentyloxy, hexyloxy, and the like;
  • halo or “halogen” used herein, either alone or in combination with other radicals, such as “haloalkyl", “perhaloalkyl” refers to a fluoro, chloro, bromo or iodo group.
  • haloalkyl denotes an alkyl radical, as defined above, substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups.
  • haloalkoxy denotes a haloalkyl, as defined above, directly attached to an oxygen atom, such as fluoromethoxy, chloromethoxy, fluoroethoxy chloroethoxy groups, and the like.
  • aryl refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings, in the poly ring systems are fused or attached to each other through a single bond.
  • Suitable aryl groups include phenyl, naphthyl, and biphenyl.
  • (CH 2 )o as employed in expressions such as "(CH2)o-4" means a direct covalent bond.
  • an integer defining the presence of certain number of atoms in a group is equal to zero, it means that the atom adjacent thereto is connected directly by a bond.
  • the present invention can be used alone or in combination with at least one agent for the treatment of cardiovascular disease and related conditions and diseases as listed herein.
  • the combination of present renin inhibitor can be made with following agents selected from the group consisting of HMG-Co-A reductase inhibitor, angiotension converting enzyme (ACE) inhibitor, calcium channel blocker, aldosterone synthase inhibitor, aldoasterone antagonist, dual angiotension converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, endothelin antagonist, angiotension II receptor blocker (ARB) and pharmaceutically acceptable salt thereof.
  • ACE angiotension converting enzyme
  • ARB angiotension II receptor blocker
  • EDAC.HC1 N-(3-Dimethyl aminopropyl)-N'-ethyl carbodiimide hydrochloride
  • DIPEA Disopropyl ethyl amine
  • MABP Mean Arterial Blood Pressure
  • HPLC purity was determined by using Agilent- 1100 instrument.
  • Wave length UV at 220 nm.
  • Polar and non polar isomers will be differentiated from HPLC t ret time and on basis of Rf on thin layer chromatography. Isomer with higher Rf value is considered non polar isomer and lower Rf value is considered as polar isomer.
  • Suitable groups and substituent's on the groups may be selected from those described anywhere in the specification.
  • Particularly useful compounds may be selected from:
  • N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer); N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
  • N-Cyclopropyl-4-(3-fluoro-4-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer); N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
  • N-Cyclopropyl-4-(3,5-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide (Non polar isomer); N-Cyclopropyl-4-(3,5-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide (Polar isomer);
  • N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride Non polar isomer
  • N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride Poly isomer
  • N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluoro-3-methylbenzamido)piperidine-3- carboxamide hydrochloride (Non polar isomer); N-Cyclopropyl-4-(4-fluoro-3-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer);
  • the compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis, or suitable variations thereon as appreciated by those skilled in the art. Referred methods include, but are not limited to those described below, where all symbols are as defined earlier.
  • 3-Carboxamido piperidine (7) may be synthesized by reacting piperidine-3-carboxylic acid (5) with amine derivative (6) where all symbols are as described earlier, by using similar procedure described for preparation of l- er/-butyl-3-ethyl-4-substituted benzamidopiperidine-l,3-dicarboxylate (4). Polar and nonpolar isomers were separated through column chromatography technique. Deprotection of Boc group in piperidine (7) may be carried out by using various Boc deprotecting reagents like TFA, dioxane.HCl, methanolic HC1 and like at temperature 0-25 °C to give corresponding salt of piperidine derivative (1).
  • the Amine building blocks [6] were synthesized by the process described beneath.
  • Amine 5 1 -(2-(3 -Methoxypropoxy)benzyl)piperazine
  • Amine 1 1 N-(2-chloro-4-((3-(3-ethoxypropoxy)benzyl)oxy)benzyl)
  • Amine 1 N-(2,3-Dimethylbenzyl)cyclopropanamine.
  • N-Cyclopropyl-2,3-dimethylbenzamide (1 eq) obtained from step 1 above was dissolved in dry THF and boron dimethyl sulfide was added dropwise at 60 0 C. After completion of reaction organic volatiles were removed in vacuo. Mixture was decomposed by addi'ng 50 % HCl solution. Mixture was basified by adding ammonia solution. Compound was extracted with EtOAc (20 V x 2). Combined organic layer was washed with water, brine, dried over sodium sulfate and removed in vacuo afforded oily compound. Crude product thus was purified by the way of flash chromatography (silica gel G; mobile phase Hexane to 50 % EtOAc in hexane). Title compound obtained as light yellow liquid.
  • Amine 3 N-((2,3-Dihydrobenzo[b][l,4]dioxin-5-yl)methyl) cyclopropanamine.
  • Amine 4 N-(Naphthalen-l-ylmethyl)cyclopropanamine.
  • Amine 6 l -(3-(3-Methoxypropoxy)benzyl)piperazine.
  • Amine 7 l-(3-Methoxypropyl)-2-(piperidin-3-yl)-lH-benzo[d]imidazole.
  • Step 1 /er/-Butyl 3-((2-aminophenyl)carbamoyl)piperidine-l-carboxylate.
  • tert-Butyl 3-((2-aminophenyl)carbamoyl)piperidine-l-carboxylate [1 eq] obtained from step 1 was treated with dil HC1 [5 vol] at 50-60°C for 3 h. Mixture was diluted with water and basify with ammonia solution to pH ⁇ 8. Compound was extracted with EtOAc. Removal of organic solvent afford yellow oil, which was than reprotected with Boc anhydride in DCM using triethyl amine as base.
  • Step 3 l -(3-Methoxypropyl)-2-(piperidin-3-yl)-lH-benzo[d]imidazole.
  • Amine 8 N-((4-Methylnaphthalen-l -yl)methyl)cyclopropanamine.
  • Amine 10 N-(4-((3-(3-methoxypropoxy)benzyl)oxy) benzyl)cyclopropanamine. Prepared similar to the procedure described in Amine 2 but using instead 4-((3- (3-methoxypropoxy)benzyl)oxy)benzaldehyde as a starting material.
  • Aminell N-(2-chloro-4-((3-(3-ethoxypropoxy)benzyl)oxy)benzyl) cyclopropanamine.
  • Amine 12 N-(2,3-Dimethoxybenzyl)cyclopropanamine.
  • Amine 13 N-(2-Methoxybenzyl)cyclopropanamine.
  • Amine 14 N-(2-(2-Methoxyethoxy)benzyl)cyclopropanamine.
  • Amine 15 N-((4-((3-(3-Methoxypropoxy)benzyl)oxy)naphthalen-l-yl)methyl) cyclopropanamine.
  • the pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (1) with suitable acids in suitable solvents by processes known in the art.
  • Step 1 ⁇ -tert-Buty ⁇ 3-ethyl 4-(3,4-difluorobenzamido)piperidine-l,3-dicarboxylate.
  • Step 2 1 -(ter/-Butoxycarbonyl)-4-(3,4-difluorobenzamido)piperidine-3-carboxylic acid.
  • Step 3 (fert-Butyl 3-(cyclopropyl(2,3-dimethylbenzyl)carbamoyl)-4-(3,4-difluoro benzamido)piperidine-l-carboxylate.
  • any reactive group in the substrate molecule may be protected, according to conventional chemical practice.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of formula (1) or pharmaceutical compositions containing them are useful as renin inhibitors suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
  • composition is provided by employing conventional techniques.
  • composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (1) according to this invention.
  • the quantity of active component, that is, the compounds of formula (1) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration.
  • the enzymatic in vitro assay was performed in 96 well polypropylene plate (Nunc), using a modified Renin inhibitor screening assay protocol (Cayman, cat no: 10006270).
  • Test compounds efficacy was determined by the percent inhibition of renin activity using Aliskiren (Tektuma) as a reference standard.
  • Guinea pigs were treated with Furosemide in drinking water (5 mg/Kg/day) for four days and intramuscular injection (10 mg/Kg) at 18 and 3 h before experiment. There after they were anaesthetized by using intramuscular injection of xylazine and ketamine (7:70 mg/Kg mixture). The left or right jugular vein was exposed and cannulated for intraperitonial [i.p.] administration of the NCEs. The left or right carotid artery was exposed and cannulated for recording blood pressure using Biopac system. 0 (vehicle control), 30 mg/kg of NCEs were administered and change in blood pressure from pretreatment was measured.
  • the compounds of the present invention are suitable as Renin inhibitors and are useful for the treatment hypertension, cardiovascular events, renal insufficiency.
  • This class of compounds showed nano molar potency in invitro fluorogenic substrate assay with an excellent PK profile which is translated in to the invivo efficacy.
  • IC5o l 1 nM with and Cmax : 1.4 ⁇ g
  • AUC(O-t) 4.67 ⁇ g
  • Pk performed at 30 mg/Kg oral dose in C57 mice.
  • In anaesthetized Guinea pig model it showed 15.7 mm reduction in blood pressure at 30 mg/kg, dose.
  • This class of compounds showed better levels in plasma compared to earlier compounds reported; it also has an advantage of low molecular weight and low Log P.

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Abstract

The present invention relates to novel renin inhibitors of general formula (1), novel intermediates involved in their synthesis, their pharmaceutically acceptable salts and pharmaceutical compositions containing them. The present invention also relates to processes for preparing compounds of general formula (1), their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.

Description

COMPOUNDS AS INHIBITORS OF RENIN
FIELD OF INVENTION
The present invention relates to novel renin inhibitors of general formula (1), novel intermediates involved in their synthesis, their pharmaceutically acceptable salts and pharmaceutical compositions containing them. The present invention also relates to processes for preparing compounds of general formula (1), their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
The Renin arfgotension aldosterone system (RAAS) is a key regulator of blood pressure (BP) as well as volume and electrolyte in both hypertensive and normotensive individual. Inappropriate activation of the RAAS is an important event/step in hypetension induced cardiovascular disease (CVD) and chronic kidney diseases (CKD). Pharmacological interruption of the RAAS is possible at three major sites, the angiotensin converting enzyme (ACE), the ATI receptor and at the interaction of renin with substrate, angiotensinogen. (Mancia et al, J Hypertension , 2007, 19(6), 1 105; Chobaniau, Hypertension, 2003,42(6), 1206)
The biologically active angiotensin II (Ang II) is generated by two step mechanism in the RAAS. The highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the action of less specific ACE. Ang -H is known to work on at least two receptor subtypes called ATI and AT2. ATI seems to transmit most of the known functions of Ang II, the role of AT2 is still unknown. Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. ACE inhibitors and ATI blockers have been accepted to treat hypertension (Waeber B. et al, "The renin-angiotensin system: role in experimental and human hypertension", in Birkenhager W. H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1986, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S). In addition, ACE inhibitors are used for renal protection (Rosenberg M. E. et al, Kidney International, 1994, 45, 403; Breyer J. A. et al. Kidney International, 1994, 45, S156), in the prevention of congestive heart failure (Vaughan D. E. et al, Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al., Am. J. Med, 1988, 8.4 (Suppl. 3A), 83) and myocardial infarction (Pfeffer M. A. et al, N. Engl. J. Med., 1992, 327, 669).
The rationale to develop renin inhibitors is the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin. In contrast, ACE can also cleave bradykinin besides Ang I and can be by-passed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 1 1, 1 155). In patients, inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Israili Z. H. et al, Annals of Internal Medicine, 1992, 1 17, 234). Chymase is not inhibited by ACE inhibitors. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors. Blockade of the ATI receptor (e.g. using losartan) on the other hand overexposes other AT-receptor subtypes (e.g. AT2) to Ang II, whose concentration is significantly increased by the blockade of ATI receptors. In summary, renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects. Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994, 12, 419; Neutel J. M. et al, Am. Heart, 1991, 122, 1094) has been created with renin inhibitors because of their insufficient oral activity due to their peptidomimetic character (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. Only few compounds containing three to four chiral centers has entered clinical trials (Rahuel J. et al. Chem. Biol, 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139, Expert. Opin. Ther.-'Pat. 2008, 18(6), 581)). Thus, renin inhibitors with good oral bioavailability and long duration of action are required. Few non-peptide renin inhibitors were described which show high in vitro activity and better pharmacokinetics profile than aliskiren (Oefner C. et al, Chem. Biol, 1999, 6, 127; Patent Application WO97/0931 1 ; Marki H. P. et al, 1 1 Farmaco, 2001, 56, 21, Olivier et al, J. Med. Chem 2009, 52(12) 3689). 3,4-Disubstituted piperidine as inhibitors of renin are reported in the literature (WO2008058387, WO2007088514). Recently Chin et al [WO 2011020193] reported 3,4-disubstituted spirocyclic piperidine as a inhibitor of renin.
The present invention relates to the identification of further renin inhibitors of a non-peptidic- nature and of low molecular weight. Described are orally active renin inhibitors of long duration, of action which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis. So, the present invention describes these non-peptidic renin inhibitors. The aim of the present invention is to improve in- vitro potency and also to overcome some of the problems in the earlier reported renin inhibitors such as problems with pharmacokinetics.
SUMMARY OF THE INVENTION
The present invention describes a group of novel compounds as renin inhibitors useful for the treatment of cardiovascular events, renal insufficiency and other related diseases. The novel compounds are defined by the general formula (1) below:
Figure imgf000004_0001
The compounds of the present invention are useful in the treatment of the human or animal body, by regulating renin levels. The compounds of this invention are therefore suitable for the treatment of cardiovascular events, renal insufficiency other related diseases.
EMBODIMENTS OF THE PRESENT INVENTION
The main objective of the present invention thus is to provide novel compounds of general formula (1), . novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures as therapeutic agen
Figure imgf000004_0002
In an embodiment is provided processes for the preparation of novel compounds of general formula (1), novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them. in another embodiment is provided pharmaceutical compositions containing compounds of general formula (1), their pharmaceutically acceptable salts, comprising pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.'
In a further embodiment is provided the use of the novel compounds of the present invention as blood pressure regulating agents, by administering a therapeutically effective and non-toxic amount of the compounds of formula (1) or their pharmaceutically acceptable compositions to the mammals.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention are defined by the general formula (I) below:
Figure imgf000005_0001
wherein Ri is optionally substituted Ct.C6 alkyl, or C3-C7 cycloalkyl groups;
R2 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, S and N, wherein when R2 is substituted, the substituents on the aryl ring or heteroaryl ring comprises of one or more substituents independently selected from the group comprising of OH, CN, NH2, halogen, oxo, OCF3, CF3, CrC6 alkyl, OC,-C6 alkyl, (CH2),.6OC,-C6 alkyl, 0-(CH2)o-4OCi-C6 alkyl, C(0)NHCi-C6 alkyl, NHC(0)C,-C6 alkyl, S(0)o.2C, -C6 alkyl, (CH2)1-6N(R4)2, (CH2)1-6NHC(=0)OR4, (CH2)1-6NHC(=0)R4, C(=0)OR4, C(=0)R4, (CH2) C(=0) NHR4, (CH2)0-40(CH2)o-4Arlj (CH2)0.4NH(CH2)o:
Figure imgf000005_0002
Preferred substituents on R2 is selected from halogen, Ci-C6 alkyl, OCi -C6 alkyl, (CH^^OC^ alkyl, O-(CH2)0-4OC, -C6 alkyl, (CH2),.6NHC(=0)OR4, (CH2),.
Figure imgf000005_0003
groups;
R3 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, S and N, wherein when R3 is substituted, the substituents are independently selected from the group comprising of oxo, OH, CN, NH2, halogen, OCF3; OCF2H, CF3j C -C alkyl, OCi-C6 alkyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, C2-C6alkenyl, Ci-C6 alkoxy, (CH2)i.6OCi-C6 alkyl, O-(CH2)0-4OCi-C6 alkyl, C(0)NHC C6 alkyl, NHC(0)C]-C6 alkyl, S(0)o.2C,-C6 alkyl, (CH2)i-6N(R )2, (CH2)i-6NHC(=0)OR4, (CH2)1-6NHC(=0)R4, C(=0)0R4, C(=0)R4, CH2(CH2)o-4C(=0)NHR4, SCO^C^ alkyl;
In a preferred embodiment of the compound of formula (I), R3 represents one of the
Figure imgf000006_0001
wherein further, each of the ring structures may be either unsubstituted or substituted with one, two or three substituents independently selected from the group consist of oxo, OH, CN, NH2, halogen, OCF3, OCF2H, CF3, Ci-C6 alkyl, OC,-C6 alkyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, C2-C6alkenyl, d-C6 alkoxy, (CH2)i-6OCi-C6 alkyl, O- (CH2)o-40C,-C6 alkyl, C(0)NHCrC6 alkyl, NHC(0)C C6 alkyl, S(O)0.2C C6 alkyl, (CH2),-6N(R4)2, (CH2),_6NHC(=0)OR4, (CH2)i-6NHC(=0)R4, C(=0)OR4, C(=0)R4, CH2(CH2)o-4C(=0)NHR4, S(0)0-2C,-C6 alkyl groups;
in an' alternate preferred embodiment of the compound of formula (I), R3 is selected from the group comprising of
Figure imgf000006_0002
wherein further, each of the ring structures may be either unsubstituted or substituted with one, two or three substituents independently selected from the group comprising of oxo, OH, CN, NH2, halogen, OCF3i OCF2H, CF3; C,-C6 alkyl, OC C6 alkyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, C2-C6alkenyl, C,-C6 alkoxy, (CH2),-6OCrC6 alkyl, 0-(CH2)o.4OCi-C6 alkyl, C(0)NHC, -C6 alkyl, NHC(0)C,-C6 alkyl, S(O)0. C C6 alkyl, (CH2),.6N(R4)2,
Figure imgf000006_0003
S(0)o-2Ci-C6 alkyl groups; ·
In a further embodiment, Ri and R2 together with the nitrogen atom to which they attached may form a saturated, unsaturated or partly saturated single or fused heterocyclic ring which may optionally contain one or more additional heteroatoms selected from N, O or S or may comprise an -SO- or an -S02-group. When the heterocyclic ring formed by Rj and R2 as defined above further comprises one or more nitrogen atom, such nitrogen atom may optionally be substituted with optionally substituted groups selected from Ci-C8 alkyl, Ci-Cg alkanoyl, optionally substituted aryl or heterocyclic group. When Ri and R2 together with the nitrogen atom forms a heterocyclic ring as define above, the heterocyclic ring may further be substituted with one or more optionally substituted aryl or heterocyclic group or the groups selected from haloalkyl, haloalkoxy, Q-Cg alkyl, OCi-C6 alkyl, (CH^Od-Ce alkyl, O-(CH2)0-4OC1-C6 alkyl, C(0)NHd-C& alkyl, NHC(0)d-C6 alkyl, S(O)0?2C,-C6 alkyl,
Figure imgf000007_0001
Figure imgf000007_0002
NHR,, (CH2)0-40(CH2)o^Ar1 , (CH2)04NH(CH2)o-4Ar1 and (CH2)i-5OAr,, (CH2)0-4 Ar,.
In a preferred embodiment, when Ri and R2 together with the nitrogen atom forms a heterocyclic ring as define above, the preferred substituents may be selected from halogen, C,-C6 alkyl, OC,-C6 alkyl, (CH2),.6OCi-C6 alkyl, O-(CH2)0-4OCi-C6 alkyl,
Figure imgf000007_0003
groups.
The term at each iteration, independently represents unsubstituted or substituted aryl or heterocyclic ring substituted with one, two, three or four substituents independently- selected from the group comprising of OH, CN, NH2, halogen, OCF3> CF3i Ci-C6alkyl, Od-Cealkyl, (CH2)i.60d-C6alkyl, O-(CH2)0-4OCrC6alkyl, C(0)NHC,-C6alkyl, NHC(0)C,-C6alkyl, S(0)o 2CrC6alkyl, (CH^N^, (CH2) NHC(=0)OR4, (CH2)i.
Figure imgf000007_0004
R4 at each occurrence is independently selected from the group comprising of hydrogen, C1-C4 alkyl group C 1-C4 haloalkyl, C3-C7 cycloalkyl groups.
As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms & also contains from 1 to 4 hetero atoms independently selected from the group consisting of N, O and S and. including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The term heterocycle as used in the specification includes both aromatic and non-aromatic single or fused cyclic system containing at least one heteroatom selected from N, O and S. The nitrogen and sulfur hetero atoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. A skilled person is well aware of the terms "heterocycle" or "heterocyclic system" and the present invention encompasses all such variations, alterations of definitions which are within the scope of such a skilled person. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. In a further optional embodiment, nitrogen in the heterocycle may optionally be quatemized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1 , then these hetero atoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7,-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyi, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H- l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1 ,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
Suitable substituents wherever applicable if not specifically defined elsewhere, includes, but are not limited to the following radicals, alone or in combination with other radicals: hydroxyl, oxo, halo, thio, nitro, amino, alkyl, alkoxy, haloalkyl or haloalkoxy groups;
In a further embodiment the groups, radicals described above may be selected from:
- the "alkyl" group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, «-propyl, i'so-propyl, n-butyl, sec-butyl, t-butyl, amyl, /-amyl, ' w-pentyl, n- . hexyl, and the like;
- The term "alkenyl" used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons; such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6- heptenyl and the like. The term "alkenyl" includes dienes and trienes of straight and branched chains;
- The term "alkynyl" used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons, such as ethynyl, 1 -propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like. The term "alkynyl" includes di- and tri-ynes;
The term "alkoxy" used herein, either alone or in combination with other radicals, denotes a radical alkyl, as defined above, attached directly to an oxygen atom, such as methoxy, ethoxy, rc-propoxy, wo-propoxy, «-butoxy, -butoxy, wo-butoxy, pentyloxy, hexyloxy, and the like;
- The term "halo" or "halogen" used herein, either alone or in combination with other radicals, such as "haloalkyl", "perhaloalkyl" refers to a fluoro, chloro, bromo or iodo group. The term "haloalkyl" denotes an alkyl radical, as defined above, substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups. The term "haloalkoxy" denotes a haloalkyl, as defined above, directly attached to an oxygen atom, such as fluoromethoxy, chloromethoxy, fluoroethoxy chloroethoxy groups, and the like.
- The term "aryl" refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings, in the poly ring systems are fused or attached to each other through a single bond. Suitable aryl groups include phenyl, naphthyl, and biphenyl.
The term "(CH2)o" as employed in expressions such as "(CH2)o-4" means a direct covalent bond. Similarly, when an integer defining the presence of certain number of atoms in a group is equal to zero, it means that the atom adjacent thereto is connected directly by a bond.
The present invention can be used alone or in combination with at least one agent for the treatment of cardiovascular disease and related conditions and diseases as listed herein. The combination of present renin inhibitor can be made with following agents selected from the group consisting of HMG-Co-A reductase inhibitor, angiotension converting enzyme (ACE) inhibitor, calcium channel blocker, aldosterone synthase inhibitor, aldoasterone antagonist, dual angiotension converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, endothelin antagonist, angiotension II receptor blocker (ARB) and pharmaceutically acceptable salt thereof. The term combination means that the component can be can be administrated together as a part of pharmaceutical composition or as part of same unitary dosage form.
List of Abbreviation
Boc: ter/-Butyloxycarbonyl
DMF: Dimethyl formamide
DCM: Dichloromethane
EDAC.HC1 : N-(3-Dimethyl aminopropyl)-N'-ethyl carbodiimide hydrochloride,
EDC: 1,2-Dichloro ethane
HOBT: 1 -Hydroxy benzotriazole
TFA: Trifluoro acetic acid
DCC: Dicyclohexylcarbodiimide
DIPEA: Disopropyl ethyl amine
EtOAc: Ethyl acetate
h: Hour(s) min: Minute(s)
tRet: Retention time '
HG1 : Hydrochloric acid
RT: Room temperature [25-30 °C]
MABP: Mean Arterial Blood Pressure
Rf : Retention factor
ACN : Acetonitrile
Instrument details
Mass spectrum was recorded on LC-MS 2010-A Shimadzu.
HPLC purity was determined by using Agilent- 1100 instrument.
HPLC condition:
HPLC Column: YMC J sphere C 18(150*4.6 mm) 4u
Mobile phase: 0.05 % TFA: ACN gradient.
Flow rate: 1.0 ml/min.
Wave length: UV at 220 nm.
Polar and non polar isomers will be differentiated from HPLC tret time and on basis of Rf on thin layer chromatography. Isomer with higher Rf value is considered non polar isomer and lower Rf value is considered as polar isomer.
Suitable groups and substituent's on the groups may be selected from those described anywhere in the specification.
Particularly useful compounds may be selected from
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride. (Polar isomer);
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2-(3- methoxypropoxy)benzyl)piperidine-3-carboxamide hydrochIoride.(Polar isomer);
3,4-Difluoro-N-(3-(4-(2-(3-methoxypropoxy)benzyl)piperazine-l-carbonyl)piperidin-4- yl)benzamide hydrochloride(Polar isomer);
3,4-Difluoro-N-(3-(4-(3-(3-methoxypropoxy)benzyl)piperazine-l-carbonyl)piperidin-4- yl)benzamide hydrochloride. (Polar isomer);
3,4-Difluoro-N-(3-(4-(3-(3-methoxypropoxy)benzyl)piperazine-l-carbonyl)piperidin-4- yl)benzamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((2,3-dihydrobenzo[b][l ,4]dioxin-5- yl)methyl)piperidine-3-carboxamide hydrochloride (Polar isomer); N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
3,4-Difluoro-N-(3 -(3«-( 1 -(3 -methoxypropy 1)- 1 H-benzo[d] im idazol-2-y l)piperidine- 1 - carbonyl)piperidin-4-yl)benzamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
4-(2-Naphthamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3-carboxamide hydrochloride (polar isomer);
N-(3-(Cyclopropyl(2,3-dimethylbenzyl)carbamoyl)piperidin-4-yl)nicotinamide hydrochloride (Polar isomer);
4-(2-Naphthamido)-N-cyclopropyl-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (polar isomer);
N-Cyclopropyl-4-(4-fluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Non Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(2,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer); N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(2,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(2,4,6-trifluorobenzamido)pip.eridine-3- . carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride. (Non polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methoxybenzamido)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methoxybenzamido)piperidine- 3-carboxamide hydrochloride (Non Polar isomer);
N-Cyclopropyl-4-(3-fluoro-4-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer); N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,3-difliiorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(2-fluoro-4-methylbenzamido)piperidine-3- carboxamide hydrochloride [Polar isomer];
N-Cyclopropyl-4-(3-fluoro-4-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methylbenzamido)piperidine-3- carboxamide hydrochloride ( on polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-((4-methylnaphthalen- 1 - yl)methyl)piperidine-3-carboxamide (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido-)rN-(-(-4^ luoronaphthalen-l - yl)methyl)piperidine-3-carboxamide (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-((4-fluoronaphthalen-l- yl)methyl)piperidine-3-carboxamide (Non Polar isomer);
N-Cyc lopropyl-4-(3 ,4-difIuorobenzamido)-N-(2,3 -dimethylbenzyl)piperidine-3 - carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(4-fluoro-2-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(4-fluoro-2-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,4-dichlorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide (Polar isomer);
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((4-fluoronaphthalen-l- yl)methyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide (Non polar isomer); N-Cyclopropyl-4-(3,5-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-(trifluoromethyl)benzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-(trifluoromethyl)benzamido)piperidine-3- carboxamide'hydrochloride (Non Polar isomer);
N-Cyclopropyl-N-(naphthalen- 1 -ylmethyl)-4-(3-
(trifIuoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer); N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3-
(trifluoromethyl)benzamido)piperidine-3-carboxamide (Non Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifluoromethyl)benzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifluoromethyl)benzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen- 1 -yimethyl)-4-(4-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer); N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifluoromethoxy)benzamido)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-CycIopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifluoromethoxy)benzamido)piperidine- 3-carboxamide hydrochloride (Non Polar isomer); ,
N-Cyclopropyl-N-(naphthalen-l-yimethyl)-4-(4-(trifluoromethoxy)benzamido) ' piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide-hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Non polar isomer); N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(5-fluoro-2-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(5-fluoro-2-methylbenzamido)piperidine-3- carboxamide hydrochloride (Non Polar isomer);
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Non Polar isomer);
N-Cyclopropyl-4-(5-fluoro-2-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(5-fluoro-2-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-
3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido.)-N-(-4^(-(3 3--methox-vpropox-v-)benzvr)oxv)~ benzyl)piperidine-3-carboxamide hydrochloride (Non polar isomer);
4- (3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide.hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(4-((3-(3-methoxypropoxy)benzyl) oxy)benzyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
4-(3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(naphthalen-l-ylmethyl)piperidine-
3- carboxamide hydrochloride (Polar isomer);
4- (3-Chloro-5-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
4-(3-Chloro-5-fluorobenzamido)-N-cyclopropyl-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluoro-3-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-(2-Chloro-4-((2-(3-methoxypropoxy)benzyl)oxy)benzyl)-N-cyclopropyl-4-(3,4- difluorobenzamido)p1peridine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluoro-3-methylbenzamido)piperidine-3- carboxamide hydrochloride (Non polar isomer); N-Cyclopropyl-4-(4-fluoro-3-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethoxybenzyl)-4-(3,5-dimethylbenzamido)piperidine-3- carboxamide hydrochloride [IJoIar isomer];
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(2-methoxybenzyl)piperidine-3- carboxamide hydrochloride [Polar isomer];
4-(3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide. hydrochloride [Non polar isomer];
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2-(2-methoxyethoxy)benzyl)piperidine- 3-carboxamide hydrochloride [Polar isomer];
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((4-((3-(3-methoxypropoxy)benzyl)oxy) naphthalen-l-yl)methyl)piperidine-3-carboxamide [Polar isomer];
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((4-((3-(3-methoxypropoxy)benzyl)oxy) naphthalen- l -yl)methyl)piperidine-3-carboxamide [Non Polar isomer].
The compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis, or suitable variations thereon as appreciated by those skilled in the art. Referred methods include, but are not limited to those described below, where all symbols are as defined earlier.
Scheme-I '
Figure imgf000017_0001
Figure imgf000017_0002
7 l-ieri-Butyl-3-ethyI-4-amido substituted piperidine-l,3-dicarboxylate (4), where all symbols are defined earlier, may be synthesized by reacting l-/er/-butyl 3-ethyl 4- aminopiperidine-l ,3-dicarboxylate (2) with acid derivative (3) where all symbols are as described earlier, using carboxyl group activating agents such as EDAC.HC1, DCC and the like in the presence of an additive HOBT and base like triethyl amine or DIPEA in solvent(s) like DMF or DCM at temperature 0-25 °C. Epimerization of 1- ½rt-butyl-3-ethyl-4-amido substituted piperidine-l,3-dicarboxylate (4) in presence of suitable base like potassium carbonate or sodium ethoxide in solvents like methanol, ethanol followed by hydrolysis of an ester group by treating with base like lithium hydroxide, sodium hydroxide, potassium carbonate and like in protic solvent like methanol or ethanol at temperature 25-80 °C afford piperidine-3-carboxylic acid derivative (5) where all symbols are as described earlier. 3-Carboxamido piperidine (7) may be synthesized by reacting piperidine-3-carboxylic acid (5) with amine derivative (6) where all symbols are as described earlier, by using similar procedure described for preparation of l- er/-butyl-3-ethyl-4-substituted benzamidopiperidine-l,3-dicarboxylate (4). Polar and nonpolar isomers were separated through column chromatography technique. Deprotection of Boc group in piperidine (7) may be carried out by using various Boc deprotecting reagents like TFA, dioxane.HCl, methanolic HC1 and like at temperature 0-25 °C to give corresponding salt of piperidine derivative (1).
The l- er/-butyl 3-ethyl 4-aminopiperidine-l,3-dicarboxylate of formula [2], where all the symbols defined earlier can be synthesized as per the general procedure mentioned in WO2006066747 along with suitable variations as are well known to a skilled person. Similarly other two isomers may be synthesized by using amine derivative of formula [2], by using (R)-l-phenylethanamine as per the general procedure mentioned in WO2006066747 along with suitable variations as are well known to a skilled person. The acid derivative [3], where all the symbols are as defined earlier can be synthesized by variety of methods known to those skilled in the art following procedure set forth in reference such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Volumes 1-21 ; R. C. LaRock, Comprehensive Organic Transformations, 2.nd edition Wiley- VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and 1. Fleming (Eds.) volumes. 1-9 Pergamon, Oxford, T991 ; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol. 1 -9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-1 1 ; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40, to name some of the known literature processes.
Preparation:
The Acid building [3] blocks were used directly from commercially available sources
Figure imgf000019_0001
The Amine building blocks [6] were synthesized by the process described beneath.
Figure imgf000019_0002
Amine 4 N-(Naphthalen- 1 -ylmethyl)cyclopropanamine
Amine 5 1 -(2-(3 -Methoxypropoxy)benzyl)piperazine
Amine 6 l-(3-(3-Methoxypropoxy)benzyl)piperazine
Amine 7 l -(3-Methoxypropyl)-2-(piperidin-3-yl)-lH-benzo[d]imidazole
Amine 8 N-((4-Methylnaphthalen- 1 -yl)methyl)cyclopropanamine
Amine 9 N-((4-Fluoronaphthalen-l-yl)methyl)cyclopropanamine
Amine 10 N-(4-((3 -(3 -methoxypropoxy)benzy l)oxy)
benzyl)cyclopropanamine
Amine 1 1 N-(2-chloro-4-((3-(3-ethoxypropoxy)benzyl)oxy)benzyl)
cyclopropanam ine
Amine 12 N-(2,3-Dimethoxybenzyl)cyclopropanamine
Amine 13 N-(2 -Methoxybenzy l)cyc lopropanam i ne
Amine 14 N-(2-(2-Methoxyethoxy)benzyl)cyclopropanamine
Amine 15 N-((4-((3-(3-Methoxypropoxy)benzyl)oxy)naphthalen-l- yl)methyl)cyclopropanamine
Amine 1: N-(2,3-Dimethylbenzyl)cyclopropanamine.
Step 1.. N-Cyclopropyl-2,3-dimethylbenzamide
To a solution of 2,3-dimethyl benzoic acid (1 eq) in DMF (5 v), was added HOBT (1. 5 eq). To this reaction mixture, was added EDAC.HCl (1.2 eq), cyclopropylamine (1.2 eq) and DIEA (1.5 eq) under N2 at 0-5 °C. The resulting reaction mixture was stirred at RT for 16 h. Mixture was quenched in water, solid obtained was filtered, dried in vacuo to afford title compound as off white solid.
Step 2: Amine 1
N-Cyclopropyl-2,3-dimethylbenzamide (1 eq) obtained from step 1 above was dissolved in dry THF and boron dimethyl sulfide was added dropwise at 60 0 C. After completion of reaction organic volatiles were removed in vacuo. Mixture was decomposed by addi'ng 50 % HCl solution. Mixture was basified by adding ammonia solution. Compound was extracted with EtOAc (20 V x 2). Combined organic layer was washed with water, brine, dried over sodium sulfate and removed in vacuo afforded oily compound. Crude product thus was purified by the way of flash chromatography (silica gel G; mobile phase Hexane to 50 % EtOAc in hexane). Title compound obtained as light yellow liquid.
Amine 2: N-(2-(3-Methoxypropoxy)benzyl) cyclopropanam ine
A mixture of 2-(3-methoxypropoxy)benzaldehyde (1 eq), cyclopropyl amine (1.2 eq) and sodium bicarbonate (1.5 eq) were heated at reftuxed in methanol (10 v) for 1 h. The reaction mixture was then cooled in ice and sodium borohydride (1.2 eq) was introduced portion wise. After complete addition mixture was allowed to warm to RT and stirred for 3 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between water and DCM. The organic , layer was separated, washed with water, dried over sodium sulfate and filtered. Concentration of the organic layer in vacuo afforded the title compound as light yellow oil. Purification of crude product thus obtained by the way of chromatography using (Silica, hexane to 40 % EtOAc in hexane) afforded title compound as light yellow oil.
Amine 3 : N-((2,3-Dihydrobenzo[b][l,4]dioxin-5-yl)methyl) cyclopropanamine.
Prepared similar to the procedure described in Amine 1 but using instead 2,3- dihydrobenzo[b][l,4]dioxine-5-carboxylic acid as a starting material.
Amine 4 : N-(Naphthalen-l-ylmethyl)cyclopropanamine.
Prepared similar to the procedure described in Amine 1 but using instead naphthalene-
1-carboxylic acid as a starting material.
Amine 5: l-(2-(3-Methoxypropoxy)benzyl)piperazine
To a solution of 2-(3-methoxypropoxy)benzaldehyde (leq), N-Boc piperidine (1 eq) and sodium bicarbonate (1.5 eq) were heated at refluxed in methanol (10 v) for 1 h. The reaction mixture was then cooled in ice and sodium borohydride (1.2 eq) was introduced portion wise. After complete addition mixture was allowed to warm to RT and stirred for 3 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over sodium sulfate and filtered. Concentration of the organic layer in vacuo afforded the title compound as light yellow oil. Purification of crude product thus obtained by the way of chromatography using (Silica, hexane to 40 % EtOAc in hexane) afforded ter/-butyl 4-(2-(3-methoxypropoxy)benzyl)piperazine-l-carboxylate which on treatment with dioxane.HCl(4M solution) in DCM afforded title compounds as off white solid.
Amine 6: l -(3-(3-Methoxypropoxy)benzyl)piperazine.
To a solution of 3-(3-methoxypropoxy)benzaldehyde (leq), N-Boc piperidine (leq) and sodium bicarbonate (1.5 eq) were heated at refluxed in methanol (10 v) for 1 h. The reaction mixture, was then cooled in ice and sodium borohydride (1.2 eq) was introduced portion wise. After complete addition mixture was allowed to warm to RT and stirred for 3 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over sodium sulfate and filtered. Concentration of the organic layer in vacuo afforded the title compound as light yellow oil. Purification of crude product thus obtained by the way of chromatography using (Silica, hexane to 40 % EtOAc in hexane) afforded /e//-butyl 4-(2^(3-methoxypropoxy)benzyl)piperazine-l-carboxylate which on treatment with dioxane.HCl(4M solution) in DCM afforded title compounds as off white solid.
Amine 7 : l-(3-Methoxypropyl)-2-(piperidin-3-yl)-lH-benzo[d]imidazole.
Step 1 : /er/-Butyl 3-((2-aminophenyl)carbamoyl)piperidine-l-carboxylate.
To a solution of l -(teri-butoxycarbonyl)piperidine-3-carboxylic acid (leq) in DMF was added o-phenylene diamine (1 eq), HOBT (1.5 eq), triethylamine (2 eq) and EDAC (1.2 eq). Mixture was allowed to stirred at RT for 16 h. Reaction mixture was quenched in water (5 V), compound was extracted with EtOAc. Removal of organic solvent under reduced pressure gave te -Butyl 3-((2^ aminophenyl)carbamoyl)piperidine-l-carboxylate as light yellow oily compounds. Step 2 : /eri-Butyl 3-£lH-benzo[d]imidazol-2-yl)piperidine-l -carboxylate.
tert-Butyl 3-((2-aminophenyl)carbamoyl)piperidine-l-carboxylate [1 eq] obtained from step 1 was treated with dil HC1 [5 vol] at 50-60°C for 3 h. Mixture was diluted with water and basify with ammonia solution to pH ~8. Compound was extracted with EtOAc. Removal of organic solvent afford yellow oil, which was than reprotected with Boc anhydride in DCM using triethyl amine as base.
Step 3 : l -(3-Methoxypropyl)-2-(piperidin-3-yl)-lH-benzo[d]imidazole.
tert-Buty[ 3-(lH-benzo[d]imidazol-2-yl)piperidine-l -carboxylate (leq) was treated with l-bromo-3-methoxypropane (1.2 eq), NaH (2.2 eq) in DMF as solvent at 10-20 °C for 3 h. Mixture was quenched in water (5v) and compound was extracted with EtOAc. Oily compound obtained from removal of organic solvent was treated with Dioxane.HCl [2V] afforded title compound as oil.
Amine 8 : N-((4-Methylnaphthalen-l -yl)methyl)cyclopropanamine.
Prepared similar to the procedure described in Amine 1 but using instead 4- methyl naphthalene- 1-carboxylic acid as a starting material.
Amine 9 : N-((4-Fluoronaphthalen-l-yl)methyl)cyclopropanamine
Prepared similar to the procedure described in Amine 1 but using instead 4-fluoro naphthalene- 1-carboxylic acid as a starting material.
Amine 10 : N-(4-((3-(3-methoxypropoxy)benzyl)oxy) benzyl)cyclopropanamine. Prepared similar to the procedure described in Amine 2 but using instead 4-((3- (3-methoxypropoxy)benzyl)oxy)benzaldehyde as a starting material.
Aminell: N-(2-chloro-4-((3-(3-ethoxypropoxy)benzyl)oxy)benzyl) cyclopropanamine.
Prepared similar to the procedure described in Amine 2 but using instead 2- chloro-4-((3-(3-ethoxypropoxy)benzyl)oxy)benzaldehyde as a starting material.
Amine 12 : N-(2,3-Dimethoxybenzyl)cyclopropanamine.
Prepared similar to the procedure described in Amine 1 but using instead 2,3- dimethoxy benzoic acid as a starting material.
Amine 13: N-(2-Methoxybenzyl)cyclopropanamine.
Prepared similar to the procedure described in Amine 1 but using instead 2- methoxy benzoic acid as a starting material.
Amine 14 : N-(2-(2-Methoxyethoxy)benzyl)cyclopropanamine.
Prepared similar to the procedure described in Amine 1 but using instead 2-(2- methoxyethoxy)benzaldehyde as a starting material.
Amine 15 : N-((4-((3-(3-Methoxypropoxy)benzyl)oxy)naphthalen-l-yl)methyl) cyclopropanamine.
Prepared similar to the procedure described in Amine 1 but using instead 4-((3- (3-methoxypropoxy)benzyl)oxy)-l -naphthoic acid as a starting material.
The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (1) with suitable acids in suitable solvents by processes known in the art.
The invention is further exemplified by the following examples below, which provides some of the several preferred embodiments of the present invention. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.
Example 1 '
Preparation of (N-cyclopropyl-4-(3,4-difluorobenzamido)-N-(2,3-dimethylbenzyl) piperidine-3-carboxamide hydrochloride. (Polar isomer)
Step 1: \ -tert-Buty\ 3-ethyl 4-(3,4-difluorobenzamido)piperidine-l,3-dicarboxylate.
To a solution of 3,4-difluoro benzoic acid [3.00 g, 18 mmol] in 60 mL DMF, was added HOBT [5.80 g, 45 mmol]. To this reaction mixture, was added EDAC.HCl [5.10 g, 27 mmol], l-/er/-butyl 3-ethyl-4-amino piperidine-l,3-dicarboxylate [5.67g, 20 mmol] and DIPEA [3.16 g, 23 mmol] under N2 at 0-5 °C. The resulting reaction mixture was stirred at 25 C for 16 h. Mixture was diluted with water. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford thick liquid compound as a mixture of diastereomers. Purification of crude product was done by the way of column chromatography (Si02, hexane to 30 % EtOAc in hexane) to get oily compound (7.6 g, 97 %). The title compound was characterized by spectral analysis ESI-MS: 435 (M+Na)+; HPLC tret : 20.27 min.
Step 2: 1 -(ter/-Butoxycarbonyl)-4-(3,4-difluorobenzamido)piperidine-3-carboxylic acid.
A solution of tert-bvAyl 3-ethyl 4-(3,4-difluorobenzamido)piperidine-l,3- dicarboxylate [7.6 g, 18.4 mmol] in methanol (5 v) and molecular sieves [4A°] was refluxed for 2 h and anhydrous potassium carbonate [7.5 g, 55 mmol] was added and mixture was refluxed for another 5 h. Mixture was filtered through hyflow. Methanol: water (4: l,(v/v)) and potassium carbonate [7.5 g, 55 mmol] was added and mixture was refluxed for 16 h. Mixture was cooled to room temperature and quenched in water. Reaction mixture was acidified to pH ~5-6 by using citric acid solution. Solid obtained was filtered, washed with water and dried. The title compound was isolated as a mixture of diastereomers as white solid (5.2 g, 73 %) and characterized by spectral analysis. ESI-MS: 406 (M+Na) +; HPLC tre, : 16.692 & 16.60 min.
Step 3: (fert-Butyl 3-(cyclopropyl(2,3-dimethylbenzyl)carbamoyl)-4-(3,4-difluoro benzamido)piperidine-l-carboxylate.
To a solution of l-(/er/-butoxycarbonyl)-4-(3,4-difluorobenzamido)piperidine-' 3-carboxylic acid [4.0 g, 10 mmol] in 25 mL DMF, was added HOBT [4.02 g, 31 mmol]. To this reaction mixture, was added EDAC.HC1 [2.99 g, 15 mmol], N-(2,3- dimethybenzyl)cyclopropanamine [2.42 g, 11 mmol] and DIPEA [1.68 g, 12 mmol] under N2 at 0-5 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. Mixture was diluted with water. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford thick liquid compound as a mixture of diastereomers. Both the diastereomers were separated by the way of column chromatography (Si02, hexane to 50 % EtOAc in hexane). Polar isomer obtained (3.38 g, 60 %) as a off white solid and characterized by spectral analysis ESI-MS : 542 (M+H)+, HPLC tret 22.02 min. Step 4 : N-Cyclopropyl-4-(3 ,4-difluorobenzamido)-N-(2,3 -dimethylbenzyl)piperidine-
3- carboxamide. (Polar isomer)
To a solution of tert-butyl 3-(cyclopropyl(2,3-dimethylbenzyl)carbamoyl)-4- (3,4-difluoro benzamido)piperidine-l-carboxylate (Polar isomer). (3.38 g, 6 mmol) in 10 v of DCM was added dioxane. HC1 (4M, 20 eq) and mixture was stirred at RT for 2 h. Removal of organic volatiles afforded the title compound as hydrochloride salt. The compound was characterized by spectral analysis. ESI-MS: 441.9 (M+H)+; HPLC tret : 14.24 min.
Several compounds of the present invention were prepared following the processes described above along with suitable modifications, alterations etc. as are within the scope of a skilled person.
Example 2:
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2-(3-methoxy
propoxy)benzyl)piperidine-3-carboxamide hydrochloride.(Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 2 and Amine 2 as a starting material. The title compound was obtained as low melting solid. ESI-MS: M+ = 502.2; HPLC tret : 14.350 min.
Example 3:
3,4-Difluoro-N-(3-(4-(2-(3-methoxypropoxy)benzyl)piperazine-l-carbonyl) piperidin- 4-yl)benzamide hydrochloride(Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 5 as a starting material. The title compound was obtained as low melting solid. ESI-MS: (M+Na)+ = 553.3; HPLC tret : 1 1.87 min.
Example 4:
3,4-Difluoro-N-(3-(4-(3-(3-methoxypropoxy)benzyl)piperazine-l-carbonyl) piperidin-
4- yl)benzamide hydrochloride. (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 6 as a starting material. The title compound was obtained as low melting solid. ESI-MS: (M+H)+ = 531.3; HPLC tret : 11.90 min.
Example 5 :
3 ,4-D ifluoro-N-(3 -(4-(3 -(3 -methoxypropoxy)benzy I)piperazine- 1 -carbonyl) piperidin-4-yl)benzamide hydrochloride (Non polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 6 as a starting material. The title compound was obtained as sticky solid. ESI- MS: (M+H) + = 531.3 ; HPLC tre, : 11.99 min.
Example 6:
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((2,3-dihydrobenzo[b][l,4] dioxin-5- yl)methyl)piperidine-3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 3 as a starting material. The title compound was obtained as off white solid. ESI-MS: (M+H)+ = 472.2; HPLC tret : 13.77 min
Example 7:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 1 and Amine 1 as a starting material. The title cotnpound was obtained as off white solid. ESI-MS: (M+) = 424; HPLC tret : 14.34 min.
Example 8:
3,4-Difluoro-N-(3-(3-(l-(3-methoxypropyl)-lH-benzo[d]imidazol-2-yl) piperidine-1 - carbonyl)piperidin-4-yl)benzamide hydrochloride. (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 7 as a starting material. The title compound was obtained as low melting solid. ESI-MS: = (M+H)+ :540.1 ; HPLC tret : 1 1.84 min.
Example 9:
N-Cyclopropyl-4-(3 ,5 -difluorobenzam ido)-N-(2,3 -dimethylbenzy 1) piperidine-3 - carboxamide hydrochloride (Polar isomer);
Prepared similar to the procedure described in Example 1 but using instead
Acid 3 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ :442.1 ; HPLC tret : 14.81 min.
Example 10:
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl) piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 3 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ :464.1 ; HPLC tret : 14.87 min. Example 11:
4-(2-Naphthamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3-carboxamide hydrochloride (polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 11 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M)+ :456.1 ; HPLC tret : 15.05 min.
Example 12:
N-(3-(cyclopropyl(2,3-dimethylbenzyl)carbamoyl)piperidin-4-yl)nicotinamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 12 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M)+ :407; HPLC tret : 1 1.64 min. "
Example 13:
4-(2-Naphthamido)-N-cyclopropyl-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 11 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M)+ :477.9; HPLC tret : 15.18 min.
Example 14 :
N-Cyclopropyl-4-(4-fluorobenzamido)-N-(naphthalen- 1 -ylmethyl) piperidine-3 - carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 1 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ :446.1 ; HPLC tre, : 14.35 min.
Example 15 :
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 7 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+Na)+ :472.0; HPLC tret : 14.66 min.
Example 16:
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 7 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ :482; HPLC tret : 14.70 min.
Example 17:
N-Cyclopropyl-N-(naphthalen-l -ylmethyl)-4-(3,4,5-trifIuorobenzamido)piperidine-3- carboxamide hydrochloride (Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 7 and Amine 4 as a starting material. The title compound was obtained as oily compound. ESI-MS: = (M+H)+ : 482; HPLC tret : 15.13 min.
Example 18:
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(2,4,5-trifluorobenzamido) piperidine-3- carboxamide hydrochloride. (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 8 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 482.2; HPLC tret : 14.32 min.
Example 19:
N-Cyclopropyl-4-(3 ,4-difluorobenzamido)-N-(naphthalen- 1 -ylmethyl)piperidine-3 - carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 4 as a starting material. The title compound was obtained as off white solid, ESI-MS:'= (M+Na)+ : 486; HPLC tret : 14.66 min.
Example 20 :
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 6 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 464.2; HPLC tret : 14.31 min.
Example 21 :
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 6 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 4421; HPLC tret : 14.23 min. Example 22:
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 6 and Amine 1 as a starting material. The title compound was obtained yellow oil. ESI-MS: = (M+H)+ : 442; HPLC tret : 14.61 min.
Example 23:
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride. (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 4 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 464.0; HPLC tret : 14.05 min.
Example 24 :
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 4 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 441.9; HPLC tret : 13.83 min.
Example 25:
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethyl benzyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 6 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 441.9; HPLC tret : 14.16 min.
Example 26:
N-Cyclopropyl-N-(naphthaIen-l -ylmethyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 7 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 482.0; HPLC tret : 13.13 min.
Example 27 :
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 6 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 442.0; HPLC tret : 14.56 min.
Example 28:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(2,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 8 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 460.0; HPLC tre, : 14.25 min
Example 29:
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(2,4,6-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 9 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 482.5; HPLC tret : 14.56 min.
Example 30:
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 4 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 442.0; HPLC tre, : 14.1 1 min.
Example 31:
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(naphthalen-l -ylmethyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 4 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+Na)+ : 464.0; HPLC tre, : 14.32 min.
Example 32 :
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(2,3-dimethylbenzyl) piperidine-3- carboxamide hydrochloride. (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 5 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+Na)+ : 442.0; HPLC tre, : 14.17 min. Example 33.:
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(2,3-dimethylbenzyl) piperidine-3- carboxamide hydrochloride. ( on polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 5 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 442.0; HPLC tret : 14.55 min.
Example 34:
N-Cyclopropyl-4-(2,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 13 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 463.9; HPLC tret : 13.89 min.
Example 35:
N-Cyclopropyl-4-(2,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 13 and Amine 4 as a starting material. The title compound was obtained as yellow oil. ESI-MS: = (M+H)+ : 463.9; HPLC tret : 14.27 min.
Example 36:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)'-4-(3-fluoro-4-methoxybenzamido)piperidine-
3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 14 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MSr= (M+H)+ : 454.10; HPLC tret : 13.75 min.
Example 37:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methoxybenzamido)piperidine- 3-carboxamide hydrochloride (Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 14 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 454.0; HPLC tret : 14.08 min.
Example 38:
N-Cyclopropyl-4-(3-fluoro-4-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 15 and Amine 4 as a starting material. The title compound was obtained as off white solid.
Figure imgf000032_0001
(M+H)+ : 460.0; HPLC tret : 14.46 min.
Example 39:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 15 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 438.0; HPLC tret : 14.35 min.
Example 40:
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 3 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 442.0; HPLC .tret : 14.57 min.
Example 41:
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 5 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 464.0 HPLC tret : 13.81 min.
Example 42:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(2-fluoro-4-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 16 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 438.10; HPLC tret : 14.23 min.
Example 43:
N-Cyclopropyl-4-(3-fluoro-4-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Non polar isomer)
Prepared similar to the procedure described in Example 1 but using instead Acid 15 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 460.0; HPLC tret : 14.92 min. Example 44:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4-methylbenzamido)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 15 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 438.0; HPLC tret : 14.80 min.
Example 45:
N-CyclopropyI-4-(2,4-difluorobenzamido)-N-((4-methylnaphthalen-l- yl)methyl)piperidine-3-carboxamide (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 6 and Amine 8 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 479.90; HPLC tre, : 14.82 min.
Example 46:
N-Cyclopropyl-4-(2,4-difluorobenzamtdo)-N-((4-fluoronaphthalen-l- yl)methyl)piperidine-3-carboxamide (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 6 and Amine 9 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 481.9; HPLC tret : 14.58 min.
Example 47:
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-((4-fluoronaphthalen-l- yl)methyl)piperidine-3-carboxamide (Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 6 and Amine 9 as a starting material. The title compound was obtained as yellow oil. ESI-MS: = (M+H)+ : 481.9; HPLC tret : 15.03 min.
Example 48:
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 6 and Amine 9 as a starting material. The title compound was obtained as sticky solid. ESI-MS: = (M+H)+ : 442.10; HPLC tret : 14.49 min.
Example 49:
N-Cyclopropyl-4-(4-fluoro-2-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 18 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 460.0; HPLC tret : 14.40 min.
Example 50:
N-Cyclopropyl-4-(4-fluoro-2-methylbenzamido)-N-(naphthalen- 1 -ylmethyl)piperidine-
3-carboxamide hydrochloride (Non Polar isomer)
Prepared similar to the procedure described in Example 1 but using instead
Acid 18 and Amine 4 as a starting material. The title compound was obtained as yellow sticky solid. ESI-MS: = (M+H)+ : 459.9; HPLC tret : 14.79 min.
Example 51:
N-Cyclopropyl-4-(3,4-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer)
Prepared similar to the procedure described in Example 1 but using instead Acid 17 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 473.9; HPLC tret : 15.29 min.
Example 52:
N-Cyclopropyl-4-(3,4-dichlorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 17 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 495.90; HPLC tret : 15.35 min.
Example 53:
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((4-fluoronaphthalen-l- yl)methyl)piperidine-3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 2 and Amine 9 as a starting material. The title compound was obtained as off white solid. ESI-MS:'= (M+H)+ : 482.0; HPLC tret : 14.58 min.
Example 54:
N-Cyclopropyl-4-(3,5-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 19 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 473.9; HPLC tret : 15.70 min. Example 55:
N-Cyclopropyl-4-(3,5-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 19 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESi-MSr= (M+H)+ : 474.0; HPLC tret : 15.38 min.
Example 56:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-(trifluoromethyl)benzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 20 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 474.1 1 ; HPLC tret : 14.93 min.
Example 57:
N-CyclopropyI-N-(2,3-dimethylbenzyl)-4-(3-(trifluoromethyl)benzamido)piperidine-3- carboxamide hydrochloride (Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 20 and Amine- l as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 474.0; HPLC tret : 15.30 min.
Example 58:
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 20 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 496.10; HPLC tret : 15.40 min.
Example 59:
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3-(trifluoromethyl)benzamido)piperidine- 3-carboxamide hydrochloride (Non Polar isomer).
Prepared sirnilar to the procedure described in Example 1 but using instead Acid 20 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 496.10; HPLC tret : 15.91 min.
Example 60:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifluoromethyl)benzamido)piperidine-3- carboxamide hydrochloride (Polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 21 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M)+ : 473.9; HPLC tret : 15.03 min.
Example 61:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifluoromethyl)benzamido)piperidine-3- carboxamide hydrochloride ( Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 21 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M)+ : 474.2; HPLC tret : 15.37 min.
Example 62:
N-Cyclopropyl-N-(naphthalen- 1 -ylmethyl)-4-(4-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 21 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 496.0; HPLC tret : 15.16 min.
Example 63:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifiuoromethoxy)benzamido)piperidine- 3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 22 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 490.3; HPLC tret : 15.30 min.
Example 64:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-(trifluoromethoxy)benzamido)piperidine- 3-carboxamide hydrochloride (Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 22 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 490.0; HPLC tret : 15.26 min.
Example 65:
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(4-(trifluoromethoxy)benzamido) piperidine-3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 22 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M)+ : 51 1.9; HPLC tret : 15.40 min. Example 66:
N-Cyclopropyl-4-(2,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 23 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 434.0; HPLC tret : 15.24 min.
Example 67:
N-Cycloprop"yl-4-(3,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 24 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 434.1 ; HPLC tret : 15.08 min.
Example 68:
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 24 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 434.1 ; HPLC tret : 14.36 min.
Example 69:
N-Cyclopropyl-4-(2,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 23 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 434.0; HPLC tret : 14.86 min.
Example 70:
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 25 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 456.4; HPLC tret : 15.36 min.
Example 71:
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 25 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 456.3; HPLC tret : 15.36 min.
Example 72:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(5-fluoro-2-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 26 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS:^= (M+H)+ : 438.4; HPLC tret : 14.35 min.
Example 73:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(5-fluoro-2-methylbenzamido)piperidine-3- carboxamide hydrochloride ( Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 26 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 438.3; HPLC tret : 14.62 min.
Example 74:
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 24 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 456.2; HPLC tret : 14.80 min.
Example 75:
N-Cyclopropy l-4-(3 ,4-dimethylbenzamido)-N-(naphthalen- 1 -ylmethyl)piperidine-3 - carboxamide hydrochloride (Non Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 24 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 456.3; HPLC tret : 15.18 min.
Example 76:
N-Cyclopropyl-4-(5 -fluoro-2-methylbenzamido)-N-(naphthalen- 1 -ylmethyl)piperidine- 3-carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 26 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 460.2; HPLC tret : 14.79 min. Example 77:
N-Cyclopropyl-4-(5 -fluoro-2-methylbenzamido)-N-(naphthalen- 1 -ylmethyi)piperidine-
3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 26 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 460.2; HPLC tret : 14.52 min.
Example 78:
N-Cyclopropy l-4-(3 , 5 -difluorobenzamido)-N-(4-((3 -(3 -methoxypropoxy)benzyl) oxy)benzyl)piperidine-3-carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 26 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 608.2; HPLC tret : 16.07 min.
Example 79:
4- (3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 27 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 458.2; HPLC tret : 14.82 min.
Example 80:
N-'Cyclopropyl-4-(3,5-difiuorobenzamido)-N-(4-((3-(3-methoxypropoxy)benzyl)oxy) benzyl)piperidine-3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 3 and Amine 10 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 608.40; HPLC tret : 15.62 min.
Example 81:
4-(3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(naphthalen-l-ylmethyl)piperidine-
3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 27 and Amine 4 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 480.1 ; HPLC tre, : 14.88 min.
Example 82:
4- (3-Chloro-5-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer). Prepared similar to the procedure described in Example 1 but using instead Acid 28 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 458.1 ; HPLC tret : 14.95 min.
Example 83:
4-(3 -Chloro-5 -fluorobenzamido)-N-cyclopropyl-N-(naphthalen- 1 -ylmethyl)piperidine-
3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 28 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+Na)+ : 502.1 ; HPLC tret : 14.97 min.
Example 84:
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluoro-3-methylbenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 29 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 438.3; HPLC tret : 14.58 min.
Example 85:
N-(2-Chloro-4-((2-(3-methoxypropoxy)benzyl)oxy)benzyl)-N-cyclopropyl-4-(3,4- difluorobenzamido)piperidine-3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 11 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 642.10; HPLC tret : 16.31 min.
Example 86:
N-Cyclopropyl-N-(2 -dimethylbenzyl)-4-(4-fluoro-3-methylbenzamido)piperidine-3- carboxamide hydrochloride (Non polar isomer).
Prepared similar to the procedure described in Example 1 but using instead
Acid 29 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 438.4; HPLC tret : 14.91 min.
Example 87:
N-Cyclopropyl-4-(4-fluoro-3-methylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer).
Prepared similar to the procedure described in Example 1 but using instead Acid 29 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 460.1 ; HPLC tret : 14.71 min. Example 88:
N-Cyclopropyl-N-(2 -dimethoxybenzyl)-4-(3,5-dimethylbenzamido)piperidine-3- carboxamide hydrochloride [Polar isomer];
Prepared similar to the procedure described in Example 1 but using instead Acid 25 and Amine 12 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 466.2; HPLC tret : 13.88 min.
Example 89 :
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(2-methoxybenzyl)piperidine-3- carboxamide hydrochloride [Polar isomer];
Prepared similar to the procedure described in Example 1 but using instead
Acid 25 and Amine 13 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 436.2; HPLC tret : 14.24 min
Example 90 : -
4-(3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride [Non polar isomer];
Prepared similar to the procedure described in Example 1 but using instead Acid 27 and Amine 1 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+H)+ : 458.1 ; HPLC tret : 15.21 min
Example 91 :
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2-(2-methoxyethoxy)benzyl)piperidine-
3-carboxamide hydrochloride [Polar isomer];
Prepared similar to the procedure described in Example 1 but using instead
Acid 2 and Amine 14 as a starting material. The title compound was obtained as off white solid. ESI-MS~= (M+Na)+ : 510.4; HPLC tret : 13.70 min.
Example 92 :
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((4-((3-(3-methoxypropoxy)benzyl)oxy) naphthalen-l-yl)methyl)piperidine-3-carboxamide [Polar isomer];
Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 15 as a starting material. The title compound was obtained as off white solid. ESI-MS: = (M+Na)+ : 680.4; HPLC tret : 16.59 min.
Example 93 :
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((4-((3-(3-methoxypropoxy)benzyl)oxy) naphthalen-l-yl)methyl)piperidine-3-carboxamide [Non Polar isomer]; Prepared similar to the procedure described in Example 1 but using instead Acid 2 and Amine 15 as a starting material. The title compound was obtained as off white solid. ESI-MSr= (M+Na)+ : 658.2; HPLC tret : 17.13 min.
It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected, according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3rd Ed., 201-245 along with references therein gives such conventional methods and are incorporated herein as references.
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (1) or pharmaceutical compositions containing them are useful as renin inhibitors suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (1) according to this invention.
The quantity of active component, that is, the compounds of formula (1) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration.
Biological Data:
In-vitro protocol for the Inhibition of human recombinant renin by the compound of invention
Procedure: The enzymatic in vitro assay was performed in 96 well polypropylene plate (Nunc), using a modified Renin inhibitor screening assay protocol (Cayman, cat no: 10006270). The reaction system comprised assay buffer containing 50 mM Tris- HCL, pH=8.0 & 100 mM sodium chloride, human recombinant renin (1 :20 diluted with fixed activity), synthetic renin substrates (Cayman, cat no: 10006906) (14.4 μΜ) and different concentrations of renin inhibitors in DMSO in a total reaction system of Ι ΟΟμί. The entire reaction mixture were incubated at 37°C for 30 mins and the fluorescence was read at excitation wavelengths of 320-360 nm and emission wavelengths of 490-520 nm. Test compounds efficacy was determined by the percent inhibition of renin activity using Aliskiren (Tektuma) as a reference standard.
The in vitro potency of several of the compounds is evaluated using Fluorogenic Substrate Assay and the IC50 values of some of the representative compounds are mentioned below.
Figure imgf000043_0001
Anaesthetized Guinea pig model.
Experimental procedure: Guinea pigs were treated with Furosemide in drinking water (5 mg/Kg/day) for four days and intramuscular injection (10 mg/Kg) at 18 and 3 h before experiment. There after they were anaesthetized by using intramuscular injection of xylazine and ketamine (7:70 mg/Kg mixture). The left or right jugular vein was exposed and cannulated for intraperitonial [i.p.] administration of the NCEs. The left or right carotid artery was exposed and cannulated for recording blood pressure using Biopac system. 0 (vehicle control), 30 mg/kg of NCEs were administered and change in blood pressure from pretreatment was measured.
Figure imgf000043_0002
Example 51 20.3
Example 52 14.3
Example 72 30.3
The compounds of the present invention are suitable as Renin inhibitors and are useful for the treatment hypertension, cardiovascular events, renal insufficiency.
This class of compounds showed nano molar potency in invitro fluorogenic substrate assay with an excellent PK profile which is translated in to the invivo efficacy. The representative example 82 showed IC5o=l 1 nM with and Cmax : 1.4 μg, AUC(O-t) : 4.67 μg, [Pk performed at 30 mg/Kg oral dose in C57 mice]. In anaesthetized Guinea pig model it showed 15.7 mm reduction in blood pressure at 30 mg/kg, dose. This class of compounds showed better levels in plasma compared to earlier compounds reported; it also has an advantage of low molecular weight and low Log P.

Claims

We claim
1. Compound represented by general formula (I) including their stereoisomers, polymorphs and also pharmaceutical compositions containing them, wherein:
Figure imgf000045_0001
Ri is optionally substituted Ci.C6 alkyl, or C3-C7 cycloalkyl groups; R2 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, S and N, or Ri and R2 together with the nitrogen atom to which they attached forms a saturated, unsaturated or partly saturated single or fused heterocyclic ring which optionally contains one or more additional heteroatoms selected from N, O or S or may comprise an -SO- or an -S02-group; R3 is an unsubstituted or substituted aryl ring, or an unsubstituted or substituted heterocyclic ring containing from 1 to 3 heteroatoms independently selected from O, S and N, wherein when R3 is substituted, the substituents are independently selected from the group comprising of oxo, OH, CN, NH2, halogen, OCF3, OCF2H, CF3, Ci-C6 alkyl, OC,-C6 alkyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, C2-C6alkenyl, d-C6 alkoxy, (CH2)i-6OCi-C6 alkyl, O-(CH2)0.4OC1-C6 alkyl, C(0)NHCrC6 alkyl, NHC(0)d-C6 alkyl, S(0)o.2C!-C6 alkyl, (CH2)1-6N(R4)2, (CH2)1-6NHC(=0)0R4, (CH2)1-6NHC(=0)R4> C(=0)OR4, C(=0)R4, CH2(CH2)o-4C(=0)NHR4, S(O)0-2C,-C6 alkyl groups wherein R4 at each occurrence is independently selected from the group comprising of hydrogen, Ci-C4 alkyl group Ci-C4 haloalkyl, C3-C7 cycloalkyl groups.
2. The compounds as claimed in claim 1 wherein R3 represents one of the following ring structures, each of which is optionally substituted with one or more substitutents as claimed in claim 1.
Figure imgf000045_0002
3. The compounds as claimed in claim 1 wherein R3 represents one of the following ring structures, each of which is optionally substituted with one or more substituents as claimed in claim 1
Figure imgf000046_0001
4. The compounds as claimed in claim 1 wherein the substituents on R2 are selected from the group comprising of OH, CN, NH2, halogen, oxo, OCF3> CF3) Ci-C6 alkyl, OC,-C6 alkyl, (CH2)wOCi--C6 alkyl, 0-(CH2)o 0Ci-C6 alkyl, C(0)NHC,-C6 alkyl, NHC(0)C,-C6 alkyl, S(O)0.2Ci-C6 alkyl, (ΟΗ2)ι.6Ν(¾)2, (CH2)i- 6NHC(=0)OR4, (CH2)1-6NHC(=0)R4, C(=0)OR4, C(=0)R4, (CH2)1-4C(=0) NHR4, (CH2)o-40(CH2)o-4Ar1 >
Figure imgf000046_0002
(CH2)o-4 A wherein the term Ατι at each iteration, independently represents unsubstituted or substituted aryl or •heterocyclyl ring & wherein all other terms are as defined earlier.
5. The compound as claimed in claim 1 wherein when i and R2 forms a heterocyclic ring which further comprises one or more nitrogen atom, such nitrogen atom are optionally substituted with optionally substituted groups selected from Ci-C8 alkyl, Ci-C8 alkanoyl, optionally substituted aryl or heterocyclic group.
6. The compound as claimed in claim 1 wherein when Ri and R2 together with the nitrogen atom forms a heterocyclic ring as defined in claim 1 , the heterocyclic ring is further substituted with one or more optionally substituted aryl or heterocyclic group or the groups selected from haloalkyl, haloalkoxy, Ci-Cg alkyl, OCi-C6 alkyl, (CH2)1-6OC,-C6 alkyl, O-(CH2)0-4OCi-C6 alkyl, C(0)NHCrC6 alkyl, NHC(0)C,-C6 alkyl, S(O)0.2C,-C6 alkyl, (CH2),.6N(R4)2, (CH2),.6NHC(=0)OR4, (CH2),.6NHC(=0) R4, C(-0)OR4 or -C(=0)R4, (CH2)i-4C(=0) NHR^ (CH2)0. 4O(CH2)0-4Ari , (CH2)0-4NH(CH2)o-4Ari and (CH2)i-5OAr1, (CH2)0-4 Αι wherein all the terms are as defined earlier.
7. The compounds as claimed in claim 1 wherein the substituents on R2 is selected from halogen, Cf-C6 alkyl, OC,-C6 alkyl, (CH2)i.6OC,-C6 alkyl, 0-(CH2)o-4OCi-C6 alkyl, (CH2)i-6NHC(=0)OR4i (CH2)1 -6NHC(=0)R4 groups, wherein all the terms are as defined earlier.
8. The compound as claimed in claim 1 wherein the substitutents on An, at each occurrence of Αη are independently selected from the group comprising of OH, CN, NH2, halogen, OCF3> CF3, C C6 alkyl, OC C6 alkyl, (CH2)i-6OCi-C6 alkyl, 0-(CH2)o-4OC1-C6 alkyl, C(0)NHC,-C6 alkyl, NHC(0)Ci-C6 alkyl, S(O)0.2Ci-C6 alkyl, (CH2),.6N(R4)2,
Figure imgf000047_0001
or - C(=0)R , CH2(CH2)o-4C(=0) NHR^ wherein all the symbols are as defined earlier.
9. The compound as claimed in claim 2 wherein the substituents on each of the rings are independently selected from the group comprising of oxo, OH, CN, NH2, halogen, OCF3, OCF2H, CF3, C C6 alkyl, OC,-C6 alkyl, C3-C6 cycloalkyl, OC3- C6 cycloalkyl, C2-C6alkenyl, Ci-Ce alkoxy, (CH2)i-6OCi-C6 alkyl, O-(CH2)0-4OC C6 alkyl, C(0)NHC,-C6 alkyl, NHC(0)C1-C6 alkyl, S(O)0.2Ci-C6 alkyl, (CH2)U 6N(R4)2, (CH2),.6NHC(=0)OR4, (CH2),.6NHC(=0)R4, C(=0)OR4, C(=0)R4, CH2(CH2)o-4C(=0)NHR4, S(O)0.2Ci-C6 alkyl groups.
10. The compound as claimed in claim 3 wherein the the substituents on each of the rings are independently selected from the group of OH, CN, NH2, halogen, OCF3> OCF2H, CF3, Ci-C6 alkyl, OCi-C6 alkyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, C2- C6alkenyl, C, -C6 alkoxy, (CH2),.6OCi-C6 alkyl, 0-(CH2)o-4OC,-C6 alkyl, C(0)NHC C6 alkyl, NHC(0)C,-C6 alkyl, S(O)0.2C,-C6 alkyl, (CH2)i.6N(R )2, (CH2)1
Figure imgf000047_0002
C(=0)R4, CH2(CH2)0. 4C(=0)NHR4i S(0)o-2C,-C6 alkyl groups
1 1. The compound as claimed in any preceding claims wherein the heterocyclic group is selected from acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l ,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5÷ oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrol inyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1 ,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl groups.
12. The compound as claimed in claim 1 selected from
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride. (Polar isomer);
N-Cyclopropyl-4'-(3,4-difluorobenzamido)-N-(2-(3- methoxypropoxy)benzyl)piperidine-3-carboxamide hydrochloride.(Polar isomer); 3,4-Difluoro-N-(3-(4-(2-(3-methoxypropoxy)benzyl)piperazine-l- carbonyl)piperidin-4-yl)benzamide hydrochloride(Polar isomer);
3,4-Difluoro-N-(3-(4-(3-(3-methoxypropoxy)benzyl)piperazine-l- carbonyl)piperidin-4-yl)benzamide hydrochloride. (Polar isomer) ;
3,4-Difluoro-N-(3-(4-(3-(3-methoxypropoxy)benzyl)piperazine-l- carbonyl)piperidin-4-yl)benzamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((2,3-dihydrobenzo[b][l,4]dioxin-5- yl)methyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
3,4-Difluoro-N-(3-(3-(l -(3-methoxypropyl)-lH-benzo[d]imidazol-2-yl)piperidine- l-carbonyl)piperidin-4-yl)benzamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
4-(2-Naphthamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (polar isomer);
N-(3-(Cyclopropyl(2,3-dimethylbenzyl)carbamoyl)piperidin-4-yl)nicotinamide hydrochloride (Polar isomer); 4-(2-Naphthamid >)-N-cyclopropyl-N-(naphthalen-l -ylrnethyl)piperidine-3- carboxamide hydrochloride (polar isomer);
N-Cyclopropyl-4-(4-fluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen-l -ylmethyl)-4-(3,4,5-trifluorobenzamido)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3,4,5-trifluorobenzamido)piperidine- 3-carboxamide hydrochloride ( on Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(2,4,5-trifluorobenzamido)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(naphthalen- 1 -y lmethyl)piperidine-3 - carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4r(2,6-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-(naphthalen-l-ylmethyI)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen- 1 -ylmethyl)-4-(3 ,4,5 -trifluorobenzamido)p iperidine- 3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,4-difIuorobenzamido)-N-(naphthalen-l -ylmethyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(2,4,5-trifluorobenzamido)piperidine-3- carboxamide hydrochloride (Polar isomer); N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(2,4,6-trifluorobenzamido)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,6-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,5-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride. (Non polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4- methoxybenzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4- methoxybenzamido)piperidine-3-carboxamide hydrochloride (Non Polar isomer); N-Cyclopropyl-4-(3-fluoro-4-methylbenzamido)-N-(naphthalen-l - ylmethyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4- methylbenzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(2,3-difluorobenzamido)-N-(naphthalen-l-ylmethyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(2-fluoro-4- methylbenzamido)piperidine-3-carboxamide hydrochloride [Polar isomer];
N-Cyclopropyl-4-(3 -fluoro-4-methylbenzamido)-N-(naphthalen- 1 - ylmethyl)piperidine-3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-fluoro-4- methylbenzamido)piperidine-3-carboxamide hydrochloride (Non polar isomer); N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-((4-methylnaphthalen-l- yl)methyl)piperidine-3-carboxamide (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-((4-fluoronaphthalen-l - yl)methyl)piperidine-3-carboxamide (Polar isomer);
N-Cyclopropyl-4-(2,4-difluorobenzamido)-N-((4-fluoronaphthalen-l- yl)methyl)piperidine-3-carboxamide (Non Polar isomer);
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-CycIopropyl-4-(4-fluoro-2-methylbenzamido)-N-(naphthalen-l- ylmethyI)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropy l-4-(4-fluoro-2-methylbenzamido)-N-(naphthalen- 1 - ylmethyl)piperidine-3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,4-dichlorobenzamido)-N-(naphthalen-l -ylmethyl)piperidine-3- carboxamide (Polar isomer);
N-Cyclopropyl-4-(3 ,4-difluorobenzamido)-N-((4-fluoronaphthalen- 1 - yl)methyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-dichlorobenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide (Non polar isomer);
N-Cycloprppy l-4-(3 ,5 -d ichlorobenzamido)-N-(2,3 -dimethylbenzy l)piper idine-3 - carboxamide (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer); .
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(3-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Non Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen-l-ylmethyl)-4-(3-
(trifluoromethyl)benzamido)piperidine-3-carboxamide (Non Polar isomer); N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(naphthalen- 1 -ylmethyl)-4-(4-
(trifluoromethyl)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-
(trifluoromethoxy)benzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-
(trifluoromethoxy)benzamido)piperidine-3-carboxamide hydrochloride (Non Polar isomer);
N-Cyclopropyl-N-(naphthalen-l -ylmethyl)-4-(4-(trifluoromethoxy)benzamido) piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(2,4-dimethylbenzamido)-N-(2,3-dimethylbenzyl)piperidine-3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(naphthalen-l-ylmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(5-fluoro-2- methylbenzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(5-fluoro-2- methylbenzamido)piperidine-3-carboxamide hydrochloride (Non Polar isomer); N-Cyclopropyl-4-(3 ,4-dimethylbenzamido)-N-(naphthalen- 1 -y lmethyl)piperidine- 3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3 ,4-dimethylbenzamido)-N-(naphthalen- 1 -ylmethyl)piperidine-
3- carboxamide hydrochloride (Non Polar isomer);
N-Cyclopropyl-4-(5 -fluoro-2-methylbenzamido)-N-(naphthalen- 1 - ylmethyl)piperidine-3-carboxamide hydrochloride (Non polar isomer);
N-Cyclopropyl-4-(5 -fluoro-2-methylbenzamido)-N-(naphthalen- 1 - ylmethyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(4-((3-(3- methoxypropoxy)benzy l)oxy) benzyl)piperidine-3 -carboxamide hydrochloride (Non polar isomer);
4- (3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-
3- carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-4-(3,5-difluorobenzamido)-N-(4-((3-(3-methoxypropoxy)benzyl) oxy)benzyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
4- (3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(naphthalen-l - ylmethyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
4-(3-Chloro-5-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine-
3- carboxamide hydrochloride (Polar isomer);
4- (3-Chloro-5-fluorobenzamido)-N-cyclopropyl-N-(naphthalen-l- ylmethyl)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluoro-3- methylbenzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-(2-Chloro-4-((2-(3-methoxypropoxy)benzyl)oxy)benzyl)-N-cyclopropyl-4-(3,4- difluorobenzamido)piperidine-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethylbenzyl)-4-(4-fluoro-3- methylbenzamido)piperidine-3-carboxamide hydrochloride (Non polar isomer); N-Cyclopropyl-4-(4-fluoro-3-methylbenzamido)-N-(naphthalen-l- ylmethyl)piperidfne-3-carboxamide hydrochloride (Polar isomer);
N-Cyclopropyl-N-(2,3-dimethoxybenzyl)-4-(3,5-dimethylbenzamido)piperidine-3- carboxamide hydrochloride [Polar isomer];
N-Cyclopropyl-4-(3,5-dimethylbenzamido)-N-(2-methoxybenzyl)piperidine-3- carboxamide hydrochloride [Polar isomer]; 4-(3-Chloro-4-fluorobenzamido)-N-cyclopropyl-N-(2,3-dimethylbenzyl)piperidine- 3-carboxamide hydrochloride [Non polar isomer];
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-(2-(2- methoxyethoxy)benzyl)piperidine-3-carboxamide hydrochloride [Polar isomer]; N-Cyclopropyl-4-(3 ,4-difluorobenzamido)-N-((4-((3 -(3 - methoxypropoxy)benzyl)oxy) naphthalen-l-yl)methyl)piperidine-3-carboxamide [Polar isomer];
N-Cyclopropyl-4-(3,4-difluorobenzamido)-N-((4-((3-(3- methoxypropoxy)benzyl)oxy) naphthalen-l-yl)methyl)piperidine-3-carboxamide [Non Polar isomer].
13. The compounds of any of the preceding claims suitably formulated into a suitable pharmaceutical composition.
14. The compounds as claimed in any preceding claim suitable as renin inhibitors.
15. The use of compounds of formula (1) for preparing pharmaceutical compositions suitable for treatment of diseases wherein the renin enzyme has a pathophysiological function.
16. The pharmaceutical composition containing renin inhibitors of the present invention.
17. The pharmaceutical composition containing the compounds of the present invention for the treatment of hypertension.
18. A method of treating hypertension and associated disease conditions by treatment with the compounds of the present invention to a person in need thereof.
19. The use of the compound of formula (I) as claimed in any preceding claims for the treatment of hypertension.
20. The compounds of the present invention including all the stereoisomers and mixtures thereof.
21. A pharmaceutical composition comprising compounds of formula (I) in combination with one or more pharmaceutically active agent selected from group consisting of HMG-Co-A reductase inhibitor, angiotension converting enzyme (ACE) inhibitor,, calcium channel blocker, aldosterone synthase inhibitor, aldoasterone antagonist, dual angiotension converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, endothelin antagonist, angiotension II receptor blocker (ARB) and pharmaceutically acceptable salts thereof.
22. The use of the pharmaceutical composition as claimed in claim 21 for the treatment of cardiovascular and other allied disorders.
23. An intermediate of formula 4 and their isomers.
Figure imgf000055_0001
wherein 3 is as defined in claim 1.
PCT/IN2012/000109 2011-12-09 2012-02-17 Compounds as inhibitors of renin WO2013084241A1 (en)

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US11339148B2 (en) 2018-01-26 2022-05-24 Idorsia Pharmaceuticals Ltd. Crystalline forms of the CXCR7 receptor antagonist (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide

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