US Pat. No. 9,777,038

PROCESS FOR PREPARING BILE ACID DERIVATIVES

Intercept Pharmaceuticals...

1. The process for preparing a compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein
the dashed bond (----) at position 7 indicates that the substituent is in a ? or ? sterochemistry;
R is hydrogen or hydroxy; and
R1 is hydrogen or C1-C6 alkyl;
comprising the step of converting a compound of formula 3A to a compound of formula 4A:
wherein Step B comprises reacting a compound of formula 3A with RuCl3, NaIO4, and an acid to form a compound of formula 4A.
US Pat. No. 10,047,117

PREPARATION AND USES OF OBETICHOLIC ACID

Intercept Pharmaceuticals...

1. A method of treating an FXR mediated disease or condition in a subject comprising administering to the subject a pharmaceutical formulation comprising an effective amount of a substantially pure solid form of obeticholic acid, wherein the solid form of obeticholic acid comprises less than 1% of chenodeoxycholic acid, and wherein the formulation comprises about 1 mg to about 30 mg of obeticholic acid.
US Pat. No. 9,238,673

PREPARATION AND USES OF OBETICHOLIC ACID

Intercept Pharmaceuticals...

1. A pharmaceutical composition comprising obeticholic acid Form 1 and a pharmaceutically acceptable carrier, wherein the
obeticholic acid Form 1 comprises less than 1% of chenodeoxycholic acid.
US Pat. No. 9,498,484

TREATMENT OF FIBROSIS USING FXR LIGANDS

Intercept Pharmaceuticals...

1. A method of treating liver fibrosis in a human not suffering from a cholestatic condition, comprising the steps of selecting
a human who is not suffering from a cholestatic condition and administering to the human 6-ethyl-chenodeoxycholic acid at
a daily dose of 5-500 mg orally.

US Pat. No. 9,090,652

BILE ACID DERIVATIVES AS FXR LIGANDS FOR THE PREVENTION OR TREATMENT OF FXR-MEDIATED DISEASES OR CONDITIONS

INTERCEPT PHARMACEUTICALS...

1. A compound selected from

US Pat. No. 10,052,337

COMPOSITIONS OF OBETICHOLIC ACID AND METHODS OF USE

Intercept Pharmaceuticals...

1. A composition comprising obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, wherein obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the particles have a diameter of 200 ?m or less.

US Pat. No. 9,540,414

TGR5 MODULATORS AND METHODS OF USE THEREOF

Intercept Pharmaceuticals...

1. A compound of formula A:

or a salt thereof, wherein:
R1 is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;

R2 is hydrogen or a-hydroxy;

R4 is substituted or unsubstituted alkyl, or halogen;

R5 is hydrogen, unsubstituted alkyl, or aryl;

R6 is hydrogen, unsubstituted or substituted alkyl, or R5 and R6 taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms;

R7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;

R11 is hydroxyl, OSO3H, OSO3?, OCOCH3, OPO3H, OPO32? or hydrogen;

R12 is hydroxyl, OSO3H, OSO3?, OCOCH3, OPO3H, OPO32? or hydrogen, or taken together R11 and R12 form a carbonyl;

m is 0, 1, or 2;
n is 0 or 1;
o is 0 or 1; and
p is 1; provided that
m+n+o=3 or 4 and
when m+n+o=3, then at least one of R5 and R6 is not hydrogen.

US Pat. No. 9,732,117

STEROIDS AS AGONISTS FOR FXR

Intercept Pharmaceuticals...

1. A pharmaceutically acceptable salt of compound of formula I:

wherein R is ethyl, or amino acid conjugate thereof,
wherein the pharmaceutically acceptable salt can be selected from a group consisting of aluminum salt, calcium salt, lithium
salt, magnesium salt, potassium salt, sodium salt, and zinc salt or N, N?-dibenzylethylenediamine salt, chlorprocaine salt,
choline salt, diethanolamine salt, ethylendiamine salt, meglumine (N-methylglucamine) salt, and procaine salt.

US Pat. No. 9,611,289

FARNESOID X RECEPTOR MODULATORS

Intercept Pharmaceuticals...

1. A compound of formula I:
or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein:
R1 is beta-hydroxyl;

R2 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more Ra;

R3 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more Rb;

R4 is alkyl, alkenyl, alkynyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more Rc;

Ra, Rb, and Rc are each independently halogen or hydroxyl;

R5 is hydroxyl, OSO3H, OSO3?, O(CO)CH3, OPO3H2, OPO32?, or hydrogen; and

R6 is hydroxyl, OSO3H, OSO3?, O(CO)CH3, OPO3H2, OPO32?, or hydrogen;

or taken together R5 and R6 with the carbon atom to which they are attached form a carbonyl.

US Pat. No. 9,243,027

TGR5 MODULATORS AND METHODS OF USE THEREOF

INTERCEPT PHARMACEUTICALS...

1. A method of ameliorating a disease or condition selected from the group consisting of diabetes, insulin resistance, insulin
hyposecretion, and pancreatic fatigue in a subject in need thereof, comprising administering to the subject a compound according
to formula A:

or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;

R2 is hydrogen or ?-hydroxy;

R3 is hydrogen, hydroxy, NH(CH2)mSO3H, or NH(CH2)nCO2H;

R4 is hydrogen, substituted or unsubstituted alkyl, or halogen;

R5 is unsubstituted or substituted alkyl, or aryl;

R6 is hydrogen, unsubstituted or substituted alkyl, or R5 and R6 taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms;

R7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;

R8 is hydrogen or substituted or unsubstituted alkyl;

R9 is hydrogen, substituted or unsubstituted alkyl, or R8 and R9 taken together form a carbonyl;

R10 is R3 or SO3H;

m is 0, 1, 2, 3, 4, or 5; and
n is 0, 1, 2, 3, 4, or 5.
US Pat. No. 9,732,116

PREPARATION AND USES OF OBETICHOLIC ACID

Intercept Pharmaceuticals...

1. A crystalline form of obeticholic acid characterized by an X-ray powder diffraction pattern comprising peaks at 9.5, 12.5
and 16.7±0.2 degrees 2-theta.

US Pat. No. 9,650,409

TGR5 MODULATORS AND METHODS OF USE THEREOF

Intercept Pharmaceuticals...

1. A method of ameliorating a disease in a subject in need thereof, comprising administering compound Ih3e:

or a pharmaceutically acceptable salt or glycine or taurine amino acid conjugate wherein the disease is selected from a metabolic
disease, wherein the metabolic disease is selected from metabolic syndrome, insulin resistance, pre-diabetic insulin resistance,
hypertension, and dyslipidemia.

US Pat. No. 9,982,008

PREPARATION AND USES OF OBETICHOLIC ACID

Intercept Pharmaceuticals...

1. A crystalline form of obeticholic acid characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 5.0±0.2 degrees 2-theta, 5.3±0.2 degrees 2-theta, and 16.8±0.2 degrees 2-theta, wherein the crystalline form of obeticholic acid is obtainable by a process comprising crystallizing crude obeticholic acid in n-butyl acetate.

US Pat. No. 10,202,414

PROCESS FOR PREPARING BILE ACID DERIVATIVES

Intercept Pharmaceuticals...

1. A process for preparing a compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein
the dashed bond (----) at position 7 indicates that the substituent is in an ? or ? stereochemistry;
R is hydrogen or hydroxy; and
R1 is hydrogen or C1-C6 alkyl,
comprising the step of
Step 4: converting a compound of formula V to a compound of formula VI:

wherein Step 4 comprises reacting a compound of formula V with RuCl3, NaIO4, and an acid to form a compound of formula VI.

US Pat. No. 9,763,964

BILE ACID DERIVATIVES AS FXR LIGANDS FOR THE PREVENTION OR TREATMENT OF FXR-MEDIATED DISEASES OR CONDITIONS

Intercept Pharmaceuticals...

1. A method of treating an FXR-mediated gastrointestinal disease or condition in a subject in need thereof, comprising administering
to the subject a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or amino acid conjugate thereof; wherein R is H, and the hydroxyl group in the 7 position
is in the alpha position; and wherein the gastrointestinal disease or condition is selected from Crohn's disease, ulcerative
colitis, post-radiation colitis, microscopic colitis, and colorectal cancer.

US Pat. No. 10,258,633

TREATMENT OF FIBROSIS USING FXR LIGANDS

Intercept Pharmaceuticals...

1. A method of treating liver fibrosis associated with alcoholic liver disease (ALD) in a human not suffering from a cholestatic condition in need thereof the method comprising the step of administering to the human 6-ethyl-chenodeoxycholic acid at a daily dose of 5-500 mg orally.
US Pat. No. 10,174,073

PREPARATION AND USES OF OBETICHOLIC ACID

Intercept Pharmaceuticals...

1. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA) comprising less than 1% by weight of chenodeoxycholic acid (CDCA), wherein the non-crystalline OCA is prepared by a process comprising at least one step of crystallizing crude OCA using at least one organic solvent.

US Pat. No. 10,532,061

FARNESOID X RECEPTOR MODULATORS

Intercept Pharmaceuticals...

1. A method of treating a chronic liver disease or condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein:
R1 is hydroxyl;
R2 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more Ra;
R3 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more Rb;
R4 is hydrogen, alkyl, alkenyl, alkynyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more Rc;
Ra, Rb, and Rc are each independently halogen or hydroxyl;
R5 is hydroxyl, OSO3H, OSO3?, OCOCH3, OPO3H, OPO32?, or hydrogen; and
R6 is hydroxyl, OSO3H, OSO3?, OCOCH3, OPO3H, OPO32?, or hydrogen;
or taken together R5 and R6 with the carbon atom to which they are attached form a carbonyl,
wherein the chronic liver disease or condition is nonalcoholic steatohepatitis (NASH).

US Pat. No. 10,421,772

STEROIDS AS AGONISTS FOR FXR

Intercept Pharmaceuticals...

1. A method for treating an FXR-mediated disease or condition in a mammal comprising administering a therapeutically effective amount of an amino acid conjugate of compound of formula (I)
wherein a compound of formula (I) can be optionally radiolabeled, to the mammal, wherein said mammal is in need of treatment of the FXR-mediated disease or condition, and wherein the disease or condition is selected from a cholestatic liver disease, atherosclerosis, arteriosclerosis, hypercholesteremia, or hyperlipidemia.

US Pat. No. 10,369,160

METHODS OF TREATING CANCER

Intercept Pharmaceuticals...

1. A method of treating or preventing hepatocellular carcinoma in a subject in need thereof comprising administering a therapeutically effective amount of Compound 1:or a pharmaceutically acceptable salt thereof.

US Pat. No. 10,570,170

METHODS FOR PREPARATION OF BILE ACIDS AND DERIVATIVES THEREOF

INTERCEPT PHARMACEUTICALS...

1. A method of preparing a compound of Formula (A):
or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:
R1 is ?-OH or an oxo group;
R2 is H, F, ?-C1-C3 alkyl optionally substituted with F or OH, ?-C1-C3 alkoxy, ?-C2-C3 alkenyl or alkynyl, cycloalkylmethylene, or cycloalkyl;
R3 and R7 are each independently H, F, or C1-C4 alkyl optionally substituted with F or OH, or R3 or R7 taken together with another R3 or R7 on an adjacent carbon atom forms a substituted or unsubstituted C1-C6 carbocyclic or heterocyclic ring;
R4, R5 and R8 are each independently H, ?-OH, or ?-OH;
R6 is CO2H, OSO3H, NH2, NHCO2(CH2CHCH)phenyl, NHCO2CH2CH3, C(O)NHOH, C(O)NH(CH2)2OH, CONH(CH2)2OSO3H, or an optionally substituted 5-member heterocycle comprising 1-4 heteroatoms selected from N, S and O; and
n is 0, 1, 2 or 3;
comprising the steps of:
(1) converting Compound 1 to Compound 7

wherein “” indicates that the OH at the C3-position or C7-position is in an ?- or ?-stereochemistry; and
(2) converting Compound 7 to a compound of Formula (A),

US Pat. No. 10,414,791

METHODS FOR PREPARATION OF BILE ACIDS AND DERIVATIVES THEREOF

Intercept Pharmaceuticals...

1. A method of preparing a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is H, ?-OH, ?-OH, or an oxo group, from compound 2 comprising the steps of:(1) converting compound 2 to compound 5

(2) converting compound 5 into compound 6:

(3) converting compound 6 into compound 9:

(4) converting compound 9 into compound 10

(5) alkylating compound 10 regioselectively and stereoselectively to yield compound 11

wherein P1 is a protecting group or H;
(6) regioselectively and stereoselectively reducing compound 11 to yield compound

wherein P2 is a protecting group; and
(7) selectively reducing compound 13 and deprotecting to yield the compound of Formula (I), wherein R1 is H; or
(8) oxidizing compound 13 regioselectively to yield compound 15
and(9) selectively reducing compound 15 and deprotecting to yield the compound of Formula (I), wherein R1 is ?-OH, ?-OH, or an oxo group.

US Pat. No. 10,550,146

METHODS FOR THE PREPARATION OF OBETICHOLIC ACID AND DERIVATIVES THEREOF

Intercept Pharmaceuticals...

1. A method of preparing obeticholic acid (OCA)or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, comprising:a) reacting Compound 2 with paraldehyde to form Compound 3:
wherein the reaction is conducted at a temperature between 10° C. and 30° C.,b) reacting Compound 3 with a base to form Compound 4:

c) hydrogenating Compound 4 to form Compound 5:
andd) reducing the keto group at the C-7 position of Compound 5 to form OCA:

US Pat. No. 10,604,544

METHODS FOR PREPARATION OF BILE ACIDS AND DERIVATIVES THEREOF

INTERCEPT PHARMACEUTICALS...

1. A method of preparing a compound of Formula (A):
or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein:
R1 is ?-OH or an oxo group;
R2 is H, F, ?-C1-C3 alkyl optionally substituted with F or OH, ?-C1-C3 alkoxy, ?-C2-C3 alkenyl or alkynyl, cycloalkylmethylene, or cycloalkyl;
R3 and R7 are each independently H, F, or C1-C4 alkyl optionally substituted with F or OH, or R3 or R7 taken together with another R3 or R7 on an adjacent carbon atom forms a substituted or unsubstituted C1-C6 carbocyclic or heterocyclic ring;
R4, R5 and R8 are each independently H, ?-OH, or ?-OH;
R6 is CO2H, OSO3H, NH2, NHCO2(CH2CHCH)phenyl, NHCO2CH2CH3, C(O)NHOH, C(O)NH(CH2)2OH, CONH(CH2)2OSO3H, or an optionally substituted 5-member heterocycle comprising 1-4 heteroatoms selected from N, S and O; and
n is 0, 1, 2 or 3;
comprising the steps of:
(1) converting Compound 1 to Compound 7

wherein “” indicates that the OH at the C3-position or C7-position is in an ?- or ?-stereochemistry; and
(2) converting Compound 7 to a compound of Formula (A),

US Pat. No. 10,548,906

METHODS OF PROMOTING HEPATIC REGENERATION

Intercept Pharmaceuticals...

1. A method of accelerating, promoting or increasing hepatic regeneration in a subject with reduced liver function, comprising administering to the subject a therapeutically effective amount of a compound of formula (A):or a pharmaceutically acceptable salt thereof, wherein:R1 is hydrogen or C1-C6 alkyl;
R2, R3, and R5 are each independently hydrogen or hydroxyl;
R6 is hydrogen;
R4 is CO2H, C(O)NH(CH2)mSO3H, C(O)NH(CH2)nCO2H, or OSO3H; and
m and n are each independently 1, 2, or 3.

US Pat. No. 10,604,545

METHODS FOR THE PREPARATION OF OBETICHOLIC ACID AND DERIVATIVES THEREOF

INTERCEPT PHARMACEUTICALS...

1. A method of preparing obeticholic acid (OCA)or a pharmaceutical acceptable salt, solvate, or amino acid conjugate thereof, comprising:alkylating the carbon atom at the C-6 position of Compound 1 with an alkylating agent to form Compound 2:
wherein PG is a protecting group, andreducing the keto group at the C-7 position of Compound 2 to form OCA:
wherein the method is conducted at a temperature above ?20° C.

US Pat. No. 10,646,499

COMPOSITIONS OF OBETICHOLIC ACID AND METHODS OF USE

Intercept Pharmaceuticals...

1. A method of treating nonalcoholic steatohepatitis (NASH) in a subject in need thereof, said method comprising administering to the subject a tablet comprising an intra-granular portion and an extra-granular portion, the intra-granular portion comprising obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof in an amount of about 1 to about 50 mg, and one or more pharmaceutically acceptable excipients, and the extra-granular portion comprising one or more pharmaceutically acceptable excipients,wherein at least one pharmaceutically acceptable excipient in the tablet has an alcohol content of less than about 6% (w/w),
wherein the amount is a starting dose, an adjusted dose or a re-adjusted dose; and
wherein the tablet is administered daily (QD), every other day (Q2D), once a week (QW), twice a week (BID), three times a week (TIW), once a month (QM), or twice a month (Q2M).

US Pat. No. 10,758,549

COMPOSITIONS OF OBETICHOLIC ACID AND METHODS OF USE

Intercept Pharmaceuticals...

1. A method of treating primary biliary cholangitis (PBC) in a subject in need thereof, said method comprising administering to the subject a tablet comprising an intra-granular portion and an extra-granular portion, the intra-granular portion comprising obeticholic acid or a pharmaceutically acceptable salt or amino acid conjugate thereof in an amount of about 1 mg to about 50 mg, and one or more pharmaceutically acceptable excipients, and the extra-granular portion comprising one or more pharmaceutically acceptable excipients,wherein at least one pharmaceutically acceptable excipient in the tablet has an alcohol content of less than about 6% (w/w);
wherein the amount is a starting dose, an adjusted dose or a re-adjusted dose; and
wherein the tablet is administered daily (QD), every other day (Q2D), once a week (QW), twice a week (BID), three times a week (TIW), once a month (QM), or twice a month (Q2M).

US Pat. No. 10,815,267

3-DESOXY DERIVATIVE AND PHARMACEUTICAL COMPOSITIONS THEREOF

Intercept Pharmaceuticals...

1. A compound of structure:
or a pharmaceutically acceptable salt or amino acid conjugate thereof.

US Pat. No. 10,800,807

TGR5 MODULATORS AND METHODS OF USE THEREOF

Intercept Pharmaceuticals...

1. A compound of formula A:or a pharmaceutically acceptable salt, ester, tautomer, or amino acid conjugate, thereof, wherein:A is
oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;n is 0, 1, or 2;
R1 is H or OH;
R2 is H or OH;
R3 is CR11R12C(O)OH, C(O)NHR31, tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O)2—(C1-C3)alkyl;
R11 and R12 are each independently H, F, OH, CH2OH, or CH2F, provided that R11 and R12 are not both H;
R31 is OH, (CH2)pOH, or (CH2)pOSO3H; and
p is 1 or 2.

US Pat. No. 10,751,349

COMPOSITIONS OF OBETICHOLIC ACID AND METHODS OF USE

Intercept Pharmaceuticals...

1. A tablet comprising obeticholic acid in an amount of 1 mg to 50 mg and a pharmaceutically acceptable excipient, wherein said obeticholic acid is in the form of jet-milled particles having a diameter of less than about 100 ?m when analyzed by laser diffraction, and wherein D50 is not more than 50 ?m, andwherein the pharmaceutically acceptable excipient has a total primary alcohol impurity of less than about 6% (wt/wt).

US Pat. No. 10,894,054

FXR AGONIST COMPOSITIONS FOR COMBINATION THERAPY

Intercept Pharmaceuticals...

1. A pharmaceutical composition comprising an FXR agonist, at least one additional therapeutic agent, and optionally one or more pharmaceutically acceptable carriers, wherein the FXR agonist is a compound of formula I:or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein:R1 is hydrogen or unsubstituted C1-C6 alkyl;
R2 is hydrogen or ?-hydroxyl;
R4 is hydroxyl or hydrogen; and
R7 is hydroxyl or hydrogen,wherein the at least one additional therapeutic agent is a GLP-1 receptor agonist selected from exenatide/exendin-4, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, BRX-0585 (Pfizer/Biorexis), and CJC-1134-PC (exendin-4 conjugated to human albumin), wherein the pharmaceutical composition is in a form for oral administration.
US Pat. No. 10,987,362

TREATMENT OF FIBROSIS USING FXR LIGANDS

Intercept Pharmaceuticals...

1. A method for treating non-alcoholic steatohepatitis in a subject not suffering from a cholestatic condition, the method comprising the step of administering to the subject an effective amount of tauro-6-ethyl-chenodeoxycholic acid (tauro-6ECDCA).