# US 8,785,635 B2 · Cyclopamine analogs

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,785,635 B2
- Document ID: US8785635B2
- Status: Granted
- Kind: B2
- Application number: 12/199,689
- Filed: 2008-08-27
- Published: 2009-01-08
- Granted: 2014-07-22
- Earliest claimed: 2006-12-28
- Assignees: Infinity Pharmaceuticals, Inc.
- Applicants: Brian Austad; Mark L. Behnke; Alfredo C. Castro; Michael J. Grogan; Somarajannair Janardanannair; Andre Lescarbeau; Stephane Peluso; Martin Tremblay
- Inventors: Brian Austad; Mark L. Behnke; Alfredo C. Castro; Michael J. Grogan; Somarajannair Janardanannair; Andre Lescarbeau; Stephane Peluso; Martin Tremblay
- Web page: https://patentgrep.com/patent/US8785635B2

## CPC

- A61K 31/4355: the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 31/664: Amides of phosphorus acids
- A61K 31/69: Boron compounds
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 38/21: Interferons {[IFN]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 307/94: spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
- C07D 471/04: Ortho-condensed systems
- C07D 471/10: Spiro-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/10: Spiro-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07J 69/00: Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07J: STEROIDS (seco-steroids C07C)

## Abstract

The invention provides novel derivatives of cyclopamine having the following formula:

## Claims

### Claim 1

A compound represented by the following structure:
or a pharmaceutically acceptable salt thereof;
wherein:
R1 is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R5, —N(R5)C(O)R5 or a sugar;
R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or 3-7 membered heterocycloalkyl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
or R1 and R2 taken together form ═O, ═S, ═N(OR), ═N(R), ═N(NR2), or ═C(R)2;
R3 is H, alkyl, alkenyl, or alkynyl;
R4 is H; alkyl; alkenyl; alkynyl; aryl; cycloalkyl; 3-7 membered heterocycloalkyl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; aralkyl; 5-6 membered heteroaryl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; heteroaralkyl, wherein the heteroaryl portion is a 5-6 membered heteroaryl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; haloalkyl; —OR; —C(O)R5; —CO2R5; —SO2R5; —C(O)N(R5)(R5); —[C(R)2]q—R5; —[(W)—N(R)C(O)]qR5; —[(W)—C(O)]qR5; —[(W)—C(O)O]qR5; —[(W)—OC(O)]qR5; —[(W)—SO2]qR5; —[(W)—N(R5)SO2]qR5; —[(W)—C(O)N(R5)]qR5; —[(W)—O]qR5; —[(W)—N(R)]qR5; —W—NR3+X−; or —[(W)—S]qR5;
wherein each W is, independently, a diradical;
each q is independently for each occurrence 1, 2, 3, 4, 5, or 6;
X− is a halide;
each R5 is, independently, H; alkyl; alkenyl; alkynyl; aryl; cycloalkyl; 3-7 membered heterocycloalkyl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; aralkyl; 5-6 membered heteroaryl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; heteroaralkyl, wherein the heteroaryl portion is a 5-6 membered heteroaryl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or —[C(R)2]p—R6; wherein p is 0-6; or any two occurrences of R5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;
each R6 is independently hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO2(R), —C(O)N(R)2, —OC(O)N(R)(R), —SO2N(R)(R), —N(R)(R), —COOR, —C(O)N(OH)(R), —OS(O)2OR, —S(O)2OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR);
each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;
provided that when R2, R3, and R4 are H; R1 is not hydroxyl or a sugar; further
provided that when R4 is hydroxyl, then R1 is not a sugar or hydroxyl; further
provided that when R4 is hydroxyl, then R1 and R2 together are not C═O.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is H, —OR, amino, sulfonamido, sulfamido, —OC(O)R5 or —N(R5)C(O)R5.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R1 is sulfonamido.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2 is H or 3-7 membered heterocycloalkyl that includes from 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R2 is H.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 and R2 taken together along with the carbon to which they are bonded form ═O, ═N(OR), or ═S.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R1 and R2 taken together along with the carbon to which they are bonded form ═O.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3 is H.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R4 is H, alkyl, hydroxyl, aralkyl, —[C(R)2]q—R5, —[(W)—N(R)C(O)]qR5, —[(W)—N(R)SO2]qR5, —[(W)—C(O)N(R)]qR5, —[(W)—O]qR5, —[(W)—C(O)]qR5 or —[(W)—C(O)O]qR5.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R4 is H, alkyl, aralkyl, —[(W)—C(O)N(R)]qR5 or —[(W)—N(R)C(O)]qR5.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R4 is H.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R1 is sulfonamido, R2 is H and R3 is H.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R1 is sulfonamido, R3 is H and R4 is H.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R1 is sulfonamido, R2 is H and R4 is H.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R2 is H, R3 is H and R4 is H.

### Claim 16 (depends on 1)

The compound of claim 1, wherein said compound is isolated.

### Claim 17 (depends on 1)

The compound of claim 1, wherein said compound is epimerically pure.

### Claim 18

A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 19

A composition comprising a mixture of
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

### Claim 21

An isolated compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 21)

The compound of claim 21, wherein said compound is epimerically pure.

### Claim 23 (depends on 21)

A pharmaceutical composition comprising a compound of claim 21, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

### Claim 24 (depends on 1)

The compound of claim 1, wherein each R5 is, independently, alkyl or aralkyl.

### Claim 25 (depends on 1)

The compound of claim 1, wherein:
R1 is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R5, —N(R5)C(O)R5 or a sugar;
R2 is H;
R1 and R2 taken together form ═O, ═S, ═N(OR);
R3 is H;
R4 is H, alkyl, hydroxyl, aralkyl, —[C(R)2]q—R5, —[(W)—N(R)C(O)]qR5, —[(W)—N(R)SO2]qR5, —[(W)—C(O)N(R)]qR5, —[(W)—O]qR5, —[(W)—C(O)]qR5 or —[(W)—C(O)O]qR5; and
each R5 is, independently, alkyl or aralkyl.

### Claim 26 (depends on 25)

The compound of claim 25, wherein R1 is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R5, —N(R5)C(O)R5 or a sugar.

### Claim 27 (depends on 25)

The compound of claim 25, wherein R1 is —OR, amino, sulfonamido, —OC(O)R5, or —N(R5)C(O)R5.

### Claim 28 (depends on 25)

The compound of claim 25, wherein R1 is sulfonamido.

### Claim 29 (depends on 25)

The compound of claim 25, wherein R1 and R2 taken together along with the carbon to which they are bonded form ═O.

### Claim 30 (depends on 25)

The compound of claim 25, wherein R4 is H, alkyl, aralkyl, —[(W)—C(O)N(R)]qR5 or —[(W)—N(R)C(O)]qR5.

### Claim 31 (depends on 26)

The compound of claim 26, wherein R4 is H, alkyl, aralkyl, —[(W)—C(O)N(R)]qR5 or —[(W)—N(R)C(O)]qR5.

### Claim 32 (depends on 27)

The compound of claim 27, wherein R4 is H, alkyl, aralkyl, —[(W)—C(O)N(R)]qR5 or —[(W)—N(R)C(O)]qR5.

### Claim 33 (depends on 28)

The compound of claim 28, wherein R4 is H, alkyl, aralkyl, —[(W)—C(O)N(R)]qR5 or —[(W)—N(R)C(O)]qR5.

### Claim 34 (depends on 25)

The compound of claim 25, wherein R4 is H.

### Claim 35 (depends on 26)

The compound of claim 26, wherein R4 is H.

### Claim 36 (depends on 27)

The compound of claim 27, wherein R4 is H.

### Claim 37 (depends on 28)

The compound of claim 28, wherein R4 is H.

### Claim 38 (depends on 25)

The compound of claim 25, wherein R5 is aralkyl.