Substituted aminopropionic derivatives as neprilysin inhibitors

• US 8,394,853 B2
• Filed: 05/27/2010
• Issued: 03/12/2013
• Est. Priority Date: 05/28/2009
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Coppola, Gary Mark, Iwaki, Yuki, Karki, Rajeshri Ganesh, Kawanami, Toshio, Ksander, Gary Michael, Mogi, Muneto, Sun, Robert
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Ivanova, Svetlana M
• Application Number:
  US12/788,766
• Publication Number:
  US 20100305131A1
• Time in Patent Office: 1,020 Days
• Field of Search: None
• US Class Current: 514/533
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 : Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/08 : for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 15/12 : for climacteric disorders
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 : for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07B 2200/05 : Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 233/47 : having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/49 : having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 233/51 : having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/56 : having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
• CPC Class Codes: C07C 233/63 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/12 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/78 : the carbon skeleton containing rings
• CPC Class Codes: C07C 237/16 : the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07C 237/22 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 255/60 : at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2602/08 : the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 271/22 : to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 275/24 : containing six-membered aromatic rings
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/51 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 239/28 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/34 : One oxygen atom
• CPC Class Codes: C07D 239/36 : as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 309/32 : having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 317/34 : Oxygen atoms

Abstract

The present invention provides a compound of formula I′;

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁵, B¹, X and n are defined herein. The invention also relates a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Claims

1. A compound of Formula I′

;

2. A compound according to claim 1 of Formula I:

3. The compound of claim 1 wherein:

R¹ is H or C_1-7alkyl;

R² for each occurrence, is independently C_1-7alkyl, halo, C_3-7cycloalkyl, hydroxy, C_1-7alkoxy, haloC_1-7alkyl, —

NR^aR^b;

wherein R^a and R^b for each occurrence are independently H or C_1-7alkyl;

R³ is A¹-C(O)X¹ or A²-R⁴;

R⁴ is C_6-20aryl or a heteroaryl, each of which can be monocyclic or bicyclic and each of which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C_1-7alkoxy, halo, C_1-7alkyl, halo-C_1-7alkyl, C_6-10aryl, heteroaryl, —

NHSO₂—

C_1-7alkyl and benzyl;

R⁵ is H; and

X and X¹ are independently OH, —

O—

C_1-7alkyl or NR^aR^b;

B¹ is —

C(O)NH—

or —

NHC(O)—

;

A¹ is a phenyl or a heteroaryl;

each of which is optionally substituted with one or more substituents independently selected from the group consisting of C_1-7alkyl, C_3-7cycloalkyl, halo-C_1-7alkyl, hydroxy, C_1-7alkoxy, halo, —

NR^aR^b, —

OCH₂CO₂H, and —

OCH₂C(O)NH₂; and

A² is a bond or a linear or branched C_1-7 alkylene;

which is optionally substituted with one or more substituents independently selected from the group consisting of halo, C_1-7alkoxy, hydroxy, O-Acetate and C_3-7cycloalkyl; and

n is 0, 1, 2, 3, 4 or 5;

wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and

each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1-5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from 0, N and S, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 having Formula II or IIA:

5. The compound of claim 1 having formula III or IIIA:

6. The compound of claim 1 wherein A¹ is an optionally substituted phenyl or heteroaryl, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 having Formula VII or VIIA:

8. The compound of claim 7 wherein A² is a bond or CH₂ or CH₂—

CH₂, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or 4 wherein R¹ is H, R² is independently halo, C_1-7alkoxy, hydroxy, C_1-7alkyl or halo-C_1-7alkyl, n is 0, 1 or 2 and X and X¹ are independently OH or —

O—

C_1-7alkyl, or a pharmaceutically acceptable salt thereof.

10. The compounds of claim 9 wherein n is 1 or 2;

R² is meta-chloro or meta-fluoro and the other optional R² group is halo, C_1-7alkyl, halo-C_1-7alkyl, hydroxy and C_1-7alkoxy, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.