# US 2014/0154232 A1 · Use of Pl3K Inhibitors for the Treatment of Obesity, Steatosis and Ageing

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- Number: US 2014/0154232 A1
- Document ID: US20140154232A1
- Status: Published application
- Kind: A1
- Application number: 13/880,893
- Filed: 2011-06-01
- Published: 2014-06-05
- Earliest claimed: 2010-10-21
- Assignees: Centro Nacional de Investigaciones Oncologicas (CNIO)
- Inventors: Manuel Serrano Marugan; Joaquin Pastor Fernández; Sonia Martínez González; Ana Ortega Molina; James R. Bischoff; Julen Oyarzabal Santamarina
- Web page: https://patentgrep.com/patent/US20140154232A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/35: having six-membered rings with one oxygen as the only ring hetero atom
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 3/04: Anorexiants; Antiobesity agents
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The first aspect of the invention relates to a phosphoinositide 3-kinase inhibitor for use in the treatment or prevention of a disease or condition associated with the expression of peroxisome proliferator-activated receptor gamma coactivator 1-α (Pgd1α) and/or uncoupling protein 1 (Thermogenin/Ucp1) in brown adipocytes. The disease or condition may be positive energy imbalance-associated, for example, obesity, an obesity-associated disease or condition, steatosis and biological aging (performance aging). Another aspect of the invention provides the use of a phosphoinositide 3-kinase inhibitor for promoting weight loss in an individual.

## Claims

### Claim 1

A method of treating or preventing a disease or condition associated with the expression of peroxisome proliferator-activated receptor gamma coactivator 1-α (Pgc1α) and/or uncoupling protein 1 (Thermogenin/Ucp1) in brown adipocytes, comprising administering to a subject in need thereof a phosphoinositide 3-kinase inhibitor.

### Claim 2 (depends on 1)

A method according to claim 1 wherein the disease or condition is an energy imbalance-associated disease or condition.

### Claim 3 (depends on 1)

A method according to claim 1 wherein the disease or condition is a positive energy imbalance-associated disease or condition.

### Claim 4 (depends on 1)

A method according to claim 1 wherein the disease or condition is selected from the group consisting of obesity, an obesity-associated disease or condition (such as Type 2 (adult-onset) diabetes, High blood pressure, Stroke Heart attack, Heart failure, Gallstones Gout and gouty arthritis, Osteoarthritis, Sleep apnea and Pickwickian syndrome), steatosis and biological aging (performance aging).

### Claim 5 (depends on 1)

A method according to claim 1 wherein the disease or condition is obesity.

### Claim 6 (depends on 1)

A method according to claim 1 wherein the disease or condition is biological aging (performance aging).

### Claim 7 (depends on 1)

A method according to claim 1 wherein the phosphoinositide 3-kinase inhibitor is:
(a) selected from the group consisting of Class I phosphoinositide 3-kinase inhibitors, Class II phosphoinositide 3-kinase inhibitors and Class III phosphoinositide 3-kinase inhibitors;
(b) a Class IA phosphoinositide 3-kinase inhibitor or a Class1B phosphoinositide 3-kinase inhibitor;
(c) a Class IA phosphoinositide 3-kinase inhibitor that inhibits isoform p110α, isoform p110β and/or isoform p110δ;
(d) a Class IA phosphoinositide 3-kinase inhibitor that inhibits isoform p110α and isoform p110δ:
(e) a Class IB phosphoinositide 3-kinase inhibitor of isoform p110γ; and/or
(f) selected from the group consisting of wortmannin, demethoxyviridin, LY294002, PX-866, palomid 529, GSK615, IC87114, phosphatase and tensin homolog (Pten), BEZ-235, BKM-120, CAL-101, CAL-263, XL-147, XL-765, GDC-0941, GSK2126458, PBI-05204, PF-4691502, SF-1126 and a compound of formula I:
wherein:
R2 and R3 independently represent:
(i) hydrogen;
(ii) Q1;
(iii) C1-12 alkyl optionally substituted by one or more substituents selected from ═O, ═S, ═N(R10a) and Q2; or
R2 or R3 may represent a fragment of formula IA,
m represents 0, 1, 2, 3, 4, 5 or 6;
each R15 represents hydrogen, halo or C1-6 alkyl optionally substituted by one or more substituents selected from E1; or
the two R15 groups together with the carbon to which the two R15 groups are attached form a 3- to 6-membered (spiro-cyclic) ring, which ring optionally contains one or more double bonds, and optionally contains a further heteroatom selected from nitrogen, sulfur and oxygen, and which ring is optionally substituted by one or more substituents selected from E2;
Ra and Rb are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a first 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring:
(a) is fused to a second ring that is either a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, a 3- to 12-membered saturated carbocyclic ring, or an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring;
(b) comprises a linker group —(C(Rx)2)p— and/or —(C(Rx)2)r—O—(C(Rx)2)s— wherein p is 1 or 2; r is 0 or 1; s is 0 or 1; and each Rx independently represents hydrogen or C1-6 alkyl; which linker group links together any two non-adjacent atoms of the first 3- to 7-membered ring to form a bridged structure; or
(c) comprises a second ring that is either a 3- to 12-membered saturated carbocyclic ring or or a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen and nitrogen, and which second ring is linked together with the first ring via a single carbon atom common to both rings to form a spiro-cycle,
all of which cyclic groups, defined by the linkage of Ra and Rb, are optionally substituted by one or more substituents selected from ═O and E3;
R4 represents hydrogen or a substituent selected from halo, —CN, —OR10b, —N(R10b)R11b, —C(O)N(R10b)R11b,C(O)R10b, C1-6 alkyl and heterocycloalky, where the alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from E4 and ═O;
but wherein at least one of R2, R3 and R4 represents a substituent other than hydrogen;
R5 represents aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from E5;
each Q1 and Q2 independently represents, on each occasion when used herein:
halo, —CN, —NO2, —N(R10a)R11a, —OR10a, —C(═Y)—R10a, —C(═Y)—OR10a, —C(═Y)N(R10a)R11a, —OC(═Y)—R10a, —OC(═Y)—OR10a, —OC(═Y)N(R10a)R11a, —OS(O)2OR10a, —OP(═Y)(OR10a)(OR11a), —OP(OR10a)(OR11a), —N(R12a)C(═Y)R11a, —N(R12a)C(═Y)OR11a, —N(R12a)C(═Y)N(R10a)R11a, NR12aS(O)2R10a, —NR12aS(O)2N(R10a)R11a, —S(O)2N(R10a)R11a, —SC(═Y)R10a, —S(O)2R10a, —SR10a, —S(O)R10a, C1-12 alkyl, heterocycloalkyl where the alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from ═O, ═S, ═N(R10a) and E6, aryl or heteroaryl, where the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from E7;
each R10a, R11a, R12a, R10b, R11b and R12b independently represent, on each occasion when used herein, hydrogen, C1-12 alkyl, heterocycloalkyl where the alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from ═O, ═S, ═N(R20) and E10, aryl or heteroaryl, where the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from E11; or
any relevant pair of R10a, R11a and R12a and/or any pair of R10b and R11b may be linked together to form a 4- to 20-membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from ═O, ═S, ═N(R20) and E12;
each E1, E2, E3, E4, E5, E6, E7, E10, E11 and E12 independently represents, on each occasion when used herein:
(i) Q4;
(ii) C1-12 alkyl optionally substituted by one or more substituents selected from ═O and Q5; or
any two E1, E2, E3, E4, E5, E6, E7, E10, E11 or E12 groups may be linked together to form a 3- to 12-membered ring, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from ═O and J1;
each Q4 and Q5 independently represent, on each occasion when used herein:
halo, —CN, —NO2, —N(R20)R21, —OR20, —C(═Y)—R20, —C(═Y)—OR20, —C(═Y)N(R20)R21, —OC(═Y)—R20, —OC(═Y)—OR20, —OC(═Y)N(R20)R21, —OS(O)2OR20, —OP(═Y)(OR20)(OR21), —OP(OR20)(OR21), —N(R22)C(═Y)R21, —N(R22)C(═Y)OR21, —N(R22)C(═Y)N(R20)R21, —NR22S(O)2R20, —NR22S(O)2N(R20)R21, —S(O)2N(R20)R21, —SC(═Y)R20, —S(O)2R20, —SR20, —S(O)R20, C1-6 alkyl, heterocycloalkyl where the alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from ═O and J2, aryl or heteroaryl, where the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from J3;
each Y independently represents, on each occasion when used herein, ═O, ═S, ═NR23 or ═N—CN;
each R20, R21, R22 and R23 independently represent, on each occasion when used herein, hydrogen, C1-6 alkyl, heterocycloalkyl where the alkyl and heterocycloalkyl groups are optionally substituted by one or more substituents selected from J4 and ═O, aryl or heteroaryl, where the aryl and heteroaryl groups are optionally substituted by one or more substituents selected from J5; or
any relevant pair of R20, R21 and R22, may be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20-membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from J6 and ═O;
each J1, J2, J3, J4, J5 and J6 independently represents, on each occasion when used herein:
(i) Q7;
(ii) C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from ═O and Q8;
each Q7 and Q8 independently represents, on each occasion when used herein:
—CN or, preferably, halo, —N(R50)R51, —OR50, —C(═Ya)—R50, —C(═Ya)—OR50, —C(═Ya)N(R50)R51, —N(R52)C(═OYa)R51, —NR52S(O)2R50, —S(O)2R50, —SR50, —S(O)R50 or C1-6 alkyl optionally substituted by one or more fluoro atoms;
each Ya independently represents, on each occasion when used herein, ═O, ═S, ═NR53 or ═N—CN;
each R50, R51, R52 and R53 independently represents, on each occasion when used herein, hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —OR60 and —N(R61)R62; or
any relevant pair of R50, R51 and R52 may be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from ═O and C1-3 alkyl;
R60, R61 and R62 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms;
or a pharmaceutically acceptable ester, amide, solvate or salt thereof.

### Claim 8 (depends on 1)

A method according to claim 1 wherein:
(a) biological aging (performance aging) is reduced;
(b) neuromuscular coordination is improved;
(c) insulin resistance is reduced; and/or
(d) wherein lifespan is increased;
compared to an otherwise equivalent individual that has not been treated with the phosphoinositide 3-kinase inhibitor.

### Claim 9 (depends on 8)

A method according to claim 8, wherein lifespan is increased independently of cancer development.

### Claim 10 (depends on 1)

A method according to claim 1, wherein:
(a) biological energy expenditure is increased,
(b) total adiposity is decreased;
(c) brown adipocyte number is increased;
(d) brown adipose tissue (BAT) weight is increased; and/or
(e) white adipose tissue (WAT) weight is decreased,
compared to an otherwise equivalent individual that has not been treated with the phosphoinositide 3-kinase inhibitor.

### Claim 11 (depends on 1)

A method according to claim 1, wherein:
(a) the expression of peroxisome proliferator-activated receptor gamma coactivator 1-α (Pgc1α) is increased in brown adipocytes;
(b) the expression of uncoupling protein 1 (Thermogenin/Ucp1) is increased in brown adipocytes;
(c) the level of active v-akt murine thymoma viral oncogene homolog 1 (Akt/PKB) is decreased in brown adipocytes;
(d) the level of active forkhead box protein O1 (FOXO1) is increased in brown adipocytes;
(e) the level of active forkhead box protein O3 (FOXO3) is increased in brown adipocytes; and/or
(f) the level of Ser/Thr phosphorylated Irs1 is decreased in white adipocytes.
compared to an otherwise equivalent individual that has not been treated with the phosphoinositide 3-kinase inhibitor.

### Claim 12 (depends on 11)

A method according to claim 11 wherein the brown adipocytes are situated in Brown Adipose Tissue (BAT) and/or White Adipose Tissue (WAT).

### Claim 13 (depends on 1)

A method according to claim 1 wherein the phosphoinositide 3-kinase inhibitor is administered in combination (either concurrently or consecutively) with an anti-obesity medication, for example, the group consisting of orlistat, sibutramine, rimonabant, metformin, exenatide, pramlintide and lorcaserin.

### Claim 14 (depends on 1)

A method according to claim 1, where the treating is promoting weight loss in an individual.