# US 12,180,222 B2 · Crystal forms of thiophene derivatives

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- Number: US 12,180,222 B2
- Document ID: US12180222B2
- Status: Granted
- Kind: B2
- Application number: 17/052,131
- Filed: 2019-04-30
- Published: 2021-07-29
- Granted: 2024-12-31
- Earliest claimed: 2018-05-02
- Assignees: Tianjin Hemay Pharmaceutical Co., Ltd.
- Applicants: Tianjin Hemay Pharmaceutical Co., Ltd
- Inventors: Donglei Zhang; Liyu Wang; Xingwen Li
- Web page: https://patentgrep.com/patent/US12180222B2

## CPC

- A61P 11/00: Drugs for disorders of the respiratory system
- C07D 495/04: Ortho-condensed systems
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed are polymorph, crystal form III and crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide.

## Claims

### Claim 1

A polymorph of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide, having characteristic peaks at diffraction angles 2θ of about 6.5°, 14.3°, 18.7°, 19.2°, 19.6°, 23.7°, 25.8°, 26.5° and 26.9° in an X-ray powder diffraction (XRPD) pattern.

### Claim 2 (depends on 1)

The polymorph of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 1, having characteristic peaks at diffraction angles 2θ of 6.5±0.2°, 14.3±0.2°, 18.7±0.2°, 19.2±0.2°, 19.6±0.2°, 23.7±0.2°, 25.8±0.2°, 26.5±0.2° and 26.9±0.2° in an X-ray powder diffraction (XRPD) pattern.

### Claim 3

Crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide, having characteristic peaks at diffraction angles 2θ of about 6.5°, 7.1°, 7.4°, 19.2°, 19.6°, 25.8° and 26.5° in an X-ray powder diffraction (XRPD) pattern.

### Claim 4 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having characteristic peaks at diffraction angles 2θ of 6.5±0.2°, 7.1±0.2°, 7.4±0.2°, 19.2±0.2°, 19.6±0.2°, 25.8±0.2° and 26.5±0.2° in an X-ray powder diffraction (XRPD) pattern.

### Claim 5 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having characteristic peaks at diffraction angles 2θ of about 6.5°, 7.1°, 7.4°, 10.3°, 13.0°, 15.0°, 16.1°, 16.5°, 17.4°, 18.7°, 19.2°, 19.6°, 20.9°, 23.7°, 25.7°, 26.5° and 26.9° in an X-ray powder diffraction (XRPD) pattern.

### Claim 6 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having characteristic peaks at diffraction angles 2θ of 6.5±0.2°, 7.1±0.2°, 7.4±0.2°, 10.3±0.2°, 13.0±0.2°, 15.0±0.2°, 16.1±0.2°, 16.5±0.2°, 17.4±0.2°, 18.7±0.2°, 19.2±0.2°, 19.6±0.2°, 20.9±0.2°, 23.7±0.2°, 25.7±0.2°, 26.5±0.2° and 26.9±0.2° in an X-ray powder diffraction (XRPD) pattern.

### Claim 7 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, wherein diffraction angle 2θ, crystal plane spacing d and relative intensity of diffraction peak in an X-ray powder diffraction (XRPD) pattern are about as follows:
2θ (°)
Crystal Plane Spacing d (Å)
Intensity (%)
6.5
13.6
100.0
7.1
12.4
37.7
7.4
11.9
45.5
19.2
4.6
61.0
19.6
4.5
31.2
25.8
3.5
64.4
26.5
3.4
41.1.

### Claim 8 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1l-yl]acetamide of claim 3, wherein diffraction angle 2θ, crystal plane spacing d and relative intensity diffraction peak in an X-ray powder diffraction (XRPD) pattern are about as follows:
2θ (°)
Crystal Plane Spacing d (Å)
Intensity (%)
6.5
13.6
100.0
7.1
12.4
37.7
7.4
11.9
45.5
10.3
8.5
26.0
13.0
6.8
23.4
15.0
5.9
18.2
16.1
5.5
19.5
16.5
5.4
24.7
17.4
5.1
19.5
18.7
4.7
22.1
19.2
4.6
61.0
19.6
4.5
31.2
20.9
4.3
20.8
23.7
3.8
15.6
25.7
3.5
64.4
26.5
3.4
41.1
26.9
3.3
27.8.

### Claim 9 (depends on 5)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 5, having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1.

### Claim 10 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having an endothermic peak at about 144.9° C. when subjected to thermal analysis using differential scanning calorimetry (DSC).

### Claim 11 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having a heat absorption peak at 144.9±6° C. when subjected to thermal analysis using differential scanning calorimetry (DSC).

### Claim 12 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having a DSC curve substantially as shown in FIG. 2 when subjected to thermal analysis using differential scanning calorimetry (DSC).

### Claim 13 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having a TGA curve substantially as shown in FIG. 3 when subjected to thermal analysis using thermogravimetric analysis (TGA).

### Claim 14 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, wherein position and intensity of absorption peak of the crystal form III in an infrared (IR) spectroscopy are about as follows:
Position of Absorption
Intensity of Absorption
Peak (cm−1)
Peak (%)
3438.68
50.99
3269.83
47.15
3083.23
64.74
2978.8
54.6
2930.97
54.46
2840.22
65.86
1756.64
27.82
1701.56
6.76
1640.14
57.36
1590.07
22.04
1556.53
33.47
1516.98
25.12
1444.77
50.77
1427.06
48.08
1393.66
40.19
1371.58
35.75
1334.05
23.59
1294.85
12.52
1267.82
18.35
1238.14
19.02
1202.22
54.7
1185.81
61.82
1138.18
18.61
1092.22
31.54
1024.47
45.11
968.8
56.09
948.32
64.79
882.85
59.92
849.85
70.81
813.02
67.24
766.79
60.19
733.72
48.87
697.07
66.48
641.87
62.48
605.18
63.14
581.86
66.77
532.48
56.84
505.55
61.44
485.04
59.79
455.79
64.11
404.51
74.33.

### Claim 15 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, having an infrared (IR) spectroscopy substantially as shown in FIG. 4.

### Claim 16 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3 that is substantially free of solvent.

### Claim 17 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3 that is substantially free of water.

### Claim 18 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3 that is pure.

### Claim 19 (depends on 3)

The crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of any one of claim 3 that is free of solvent and water.

### Claim 20

Crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide, having characteristic peaks at diffraction angles 2θ of about 8.5°, 14.2°, 15.5°, 16.8°, 17.9°, 18.3°, 18.7°, 19.1°, 24.5° and 25.7° in an X-ray powder diffraction (XRPD) pattern.

### Claim 21 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, having characteristic peaks at diffraction angles 2θ of 8.5±0.2°, 14.2±0.2°, 15.5±0.2°, 16.8±0.2°, 17.9±0.2°, 18.3±0.2°, 18.7±0.2°, 19.1±0.2°, 24.5±0.2° and 25.7±0.2° in an X-ray powder diffraction (XRPD) pattern.

### Claim 22 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, having characteristic peaks at diffraction angles 2θ of about 6.8°, 8.5°, 13.9°, 14.2°, 15.5°, 16.8°, 17.9°, 18.3°, 18.7°, 19.1°, 19.7°, 21.8°, 22.5°, 23.5°, 24.5°, 25.7°, 26.3°, 26.8°, 27.1°, 27.8° and 28.5° in an X-ray powder diffraction (XRPD) pattern.

### Claim 23 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, having characteristic peaks at diffraction angles 2θ of 6.8±0.2°, 8.5±0.2°, 13.9±0.2°, 14.2±0.2°, 15.5±0.2°, 16.8±0.2°, 17.9±0.2°, 18.3±0.2°, 18.7±0.2°, 19.1±0.2°, 19.7±0.2°, 21.8±0.2°, 22.5±0.2°, 23.5±0.2°, 24.5±0.2°, 25.7±0.2°, 26.3±0.2°, 26.8±0.2°, 27.1±0.2°, 27.8±0.2° and 28.5±0.2° in an X-ray powder diffraction (XRPD) pattern.

### Claim 24 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, wherein diffraction angle 2θ, crystal plane spacing d and relative intensity of diffraction peak in an X-ray powder diffraction (XRPD) pattern are about as follows:
2θ (°)
Crystal Plane Spacing d (Å)
Intensity (%)
6.8
13.0
25.7
8.5
10.4
60.5
13.9
6.4
31.6
14.2
6.2
93.4
15.5
5.7
62.6
16.8
5.3
86.5
17.9
5.0
76.5
18.3
4.8
77.1
18.7
4.7
62.9
19.1
4.7
51.5
19.7
4.5
15.8
21.8
4.1
24.6
22.5
4.0
44.3
23.5
3.8
30.4
24.5
3.6
91.4
25.7
3.5
100.0
26.3
3.4
26.2
26.8
3.3
19.1
27.1
3.3
28.2
27.8
3.2
26.3
28.5
3.1
19.9.

### Claim 25 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 5.

### Claim 26 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, having an endothermic peak at about 180.8° C. when subjected to thermal analysis using differential scanning calorimetry (DSC).

### Claim 27 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, having a heat absorption peak at 180.8±6° C. when subjected to thermal analysis using differential scanning calorimetry (DSC).

### Claim 28 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, having a DSC curve substantially as shown in FIG. 6 when subjected to thermal analysis using differential scanning calorimetry (DSC).

### Claim 29 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20 that is substantially free of solvent.

### Claim 30 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20 that is substantially free of water.

### Claim 31 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20 that is substantially-pure.

### Claim 32 (depends on 20)

The crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20 that is free of solvent and water.

### Claim 33 (depends on 1)

A pharmaceutical composition, comprising the polymorph of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

### Claim 34 (depends on 33)

The pharmaceutical composition of claim 33, formulated as tablet, solution, granule, patch, ointment, gel, capsule, aerosol or suppository administered via parenteral, transdermal, mucosa, nasal, buccal, sublingual or oral route.

### Claim 35 (depends on 3)

A process for preparing the crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3, comprising crystallizing (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide in methanol to obtain the crystal form III.

### Claim 36 (depends on 35)

The process of claim 35, comprising:
dissolving (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide in methanol until completely dissolved; and
filtering and heating filtrate to 40° C. to 60° C. to precipitate the crystal form III.

### Claim 37 (depends on 20)

A process for preparing the crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20, comprising stirring (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide in acetic anhydride and evaporating under atmospheric pressure to obtain the crystal form IV.

### Claim 38 (depends on 37)

The process of claim 37, comprising:
dissolving (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide in acetic anhydride until completely dissolved; and
filtering and stirring filtrate at 60° C. under atmospheric pressure and evaporating to precipitate the crystal form IV.

### Claim 39 (depends on 1)

A method for inhibiting or relieving a disease or condition mediated by PDE4 enzyme, comprising administering a therapeutically effective amount of the polymorph of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 1 to a subject in need thereof.

### Claim 40 (depends on 39)

The method of claim 39, wherein the subject is a mammal.

### Claim 41 (depends on 39)

The method of claim 39, wherein the disease or condition is selected from the group consisting of an inflammatory disease or condition, an infectious disease or condition, an immune disease or condition, and a cancer disease or condition.

### Claim 42 (depends on 39)

The method of claim 39, wherein the disease or condition is selected from the group consisting of head carcinoma, thyroid carcinoma, neck cancer, eye cancer, skin cancer, oral cancer, throat cancer, esophagus cancer, breast cancer, bone cancer, leukemia, myeloma, lung cancer, colon cancer, carcinoma of sigmoid, rectal cancer, gastric cancer, prostate cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer, pancreatic cancer, brain cancer, intestinal cancer, heart cancer, adrenal carcinoma, subcutaneous tissue cancer, lymph node cancer, malinant melanoma, malignant glioma, HIV, hepatitis, adult respiratory distress syndrome, bone absorption disease, chronic obstructive pulmonary disease, chronic pneumonia, dermatitis, inflammatory skin disease, atopic dermatitis, cysticfibrosis, septic shock, pyaemia, endotoxin shock, blood dynamic shock, septic disease syndrome, ischemia reperfusion injury, meningitis, psoriasis, fibrosis disease, cachexia, graft rejection of graft versus host disease, autoimmunity disease, rheumatoid spondylitis, arthritis symptom, rheumatoid arthritis, osteoarthritis, osteoporosis, Crohn's disease, ulcerative colitis, enteritis, multiple sclerosis, systemic lupus erythematosus, erythema nodosum leprosum of leprosy (ENL), radiation damage, asthma, oxygen enriched lung injury, microorganism infections and microorganism infection syndrome.

### Claim 43 (depends on 3)

A method for reducing PDE4 activity, comprises administering a therapeutically effective amount of the crystal form III of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 3 to a subject in need thereof.

### Claim 44 (depends on 20)

A method for reducing PDE4 activity, comprises administering a therapeutically effective amount of the crystal form IV of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of claim 20 to a subject in need thereof.